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Impact of NAFLD and its pharmacotherapy on lipid profile and CVD

  • Author Footnotes
    1 These authors contributed equally to this work.
    Zhenya Wang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Institute of Model Animal, Wuhan University, Wuhan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Mao Ye
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Cardiology, Huanggang Central Hospital, HuBei Province, China

    Huanggang Institute of Translational Medicine, Huanggang, China
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  • Xiao-Jing Zhang
    Affiliations
    Institute of Model Animal, Wuhan University, Wuhan, China

    School of Basic Medical Sciences, Wuhan University, Wuhan, China
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  • Peng Zhang
    Affiliations
    Institute of Model Animal, Wuhan University, Wuhan, China

    School of Basic Medical Sciences, Wuhan University, Wuhan, China
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  • Jingjing Cai
    Affiliations
    Institute of Model Animal, Wuhan University, Wuhan, China

    Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
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  • Hongliang Li
    Correspondence
    Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University,Luojia Mount Wuchang, Wuhan; 430072, China.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Institute of Model Animal, Wuhan University, Wuhan, China

    Huanggang Institute of Translational Medicine, Huanggang, China
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  • Zhi-Gang She
    Correspondence
    Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, 430072, China.
    Affiliations
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Institute of Model Animal, Wuhan University, Wuhan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:July 18, 2022DOI:https://doi.org/10.1016/j.atherosclerosis.2022.07.010

      Highlights

      • Nonalcoholic fatty liver disease has emerged as a driver of atherosclerotic cardiovascular disease.
      • Acetyl-coenzyme A carboxylase inhibitors and farnesoid X receptor agonists disrupt the circulating lipid profile, which may increase the risk of atherosclerotic cardiovascular disease.
      • A novel molecule, IMA-1, moderately represses acetyl-coenzyme A carboxylase 1 activity and has promising potential in treating nonalcoholic steatohepatitis without causing a significant decrease in polyunsaturated fatty acid levels or hyperlipidemia.

      Abstract

      Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Increasing evidence suggests that, in addition to traditional metabolic risk factors such as obesity, hypercholesterolemia, hypertension, diabetes mellitus, and insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) is an emerging driver of ASCVD via multiple mechanisms, mainly by disrupting lipid metabolism. The lack of pharmaceutical treatment has spurred substantial investment in the research and development of NAFLD drugs. However, many reagents with promising therapeutic potential for NAFLD also have considerable impacts on the circulating lipid profile. In this review, we first summarize the mechanisms linking lipid dysregulation in NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NAFLD without the unwanted side effects.

      Graphical abstract

      Keywords

      1. Introduction

      Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide [
      • Virani S.S.
      • Alonso A.
      • Aparicio H.J.
      • Benjamin E.J.
      • Bittencourt M.S.
      • et al.
      Heart disease and stroke statistics-2021 update: a report from the American heart association.
      ]. The overall prevalence of ASCVD and the number of deaths due to ischemic heart disease (IHD) has risen steadily in recent decades, reaching 197 million and 9.14 million in 2019, respectively [
      • Roth G.A.
      • Mensah G.A.
      • Johnson C.O.
      • Addolorato G.
      • Ammirati E.
      • et al.
      Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.
      ,
      • Wang W.
      • Hu M.
      • Liu H.
      • Zhang X.
      • Li H.
      • et al.
      Global Burden of Disease Study 2019 suggests that metabolic risk factors are the leading drivers of the burden of ischemic heart disease.
      ]. Due to rapid economic growth and transitions in lifestyle, metabolic risk factors, such as obesity, hypercholesteremia, hypertension, diabetes mellitus, and insulin resistance (IR), have become the leading drivers of ASCVD [
      • Herrington W.
      • Lacey B.
      • Sherliker P.
      • Armitage J.
      • Lewington S.
      Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease.
      ]. Although we observed significant reductions in the prevalence and mortality rate of ASCVD in many developed countries after a comprehensive intervention in major metabolic risk factors, the number of cases and the incidence of ASCVD continue to show increasing trends throughout the rest of the world. These trends indicate that a number of remaining metabolic risk factors need to be managed more appropriately.
      As the most common chronic liver disease, nonalcoholic fatty liver disease (NAFLD) has a global prevalence of 25.24%, and its incidence is still rising [
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • et al.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Hoebinger C.
      • Rajcic D.
      • Hendrikx T.
      Oxidized lipids: common immunogenic drivers of non-alcoholic fatty liver disease and atherosclerosis.
      ]. Over one-third of patients with simple steatosis progress to a more severe form, nonalcoholic steatohepatitis (NASH), which largely increases the risk of developing liver fibrosis and cancer [
      • Qu W.
      • Ma T.
      • Cai J.
      • Zhang X.
      • Zhang P.
      • et al.
      Liver fibrosis and MAFLD: from molecular aspects to novel pharmacological strategies.
      ]. More importantly, the liver regulates systemic glucose and lipid metabolism, and its pathology enhances lipid dysregulation and IR [
      • Watt M.J.
      • Miotto P.M.
      • De Nardo W.
      • Montgomery M.K.
      The liver as an endocrine organ-linking NAFLD and insulin resistance.
      ]. Both the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines recommend that patients with NAFLD should be screened for cardiovascular disease (CVD) and that risk factors for CVD need to be aggressively controlled in these patients [
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      ,
      • Rinella M.E.
      • Tacke F.
      • Sanyal A.J.
      • Anstee Q.M.
      o.b.o.t.p.o.t.A.E. Workshop
      Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
      ]. Existing evidence from cross-sectional and longitudinal studies showed a close correlation between NAFLD and various forms of CVD [
      • Zhou J.
      • Bai L.
      • Zhang X.J.
      • Li H.
      • Cai J.
      Nonalcoholic fatty liver disease and cardiac remodeling risk: pathophysiological mechanisms and clinical implications.
      ,
      • Chen Z.
      • Liu J.
      • Zhou F.
      • Li H.
      • Zhang X.J.
      • et al.
      Nonalcoholic fatty liver disease: an emerging driver of cardiac arrhythmia.
      ,
      • Cai J.
      • Zhang X.J.
      • Ji Y.X.
      • Zhang P.
      • She Z.G.
      • et al.
      Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases.
      ,
      • Lee H.H.
      • Cho Y.
      • Choi Y.J.
      • Huh B.W.
      • Lee B.W.
      • et al.
      Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.
      ,
      • Oni E.
      • Budoff M.J.
      • Zeb I.
      • Li D.
      • Veledar E.
      • et al.
      Nonalcoholic fatty liver disease is associated with arterial distensibility and carotid intima-media thickness: (from the multi-ethnic study of atherosclerosis).
      ,
      • Hsiao C.C.
      • Teng P.H.
      • Wu Y.J.
      • Shen Y.W.
      • Mar G.Y.
      • et al.
      Severe, but not mild to moderate, non-alcoholic fatty liver disease associated with increased risk of subclinical coronary atherosclerosis.
      ], and experimental studies also provide support from a mechanistic perspective that NAFLD promotes the initiation and progression of ASCVD; however, a causal relationship has not been well established in a large population study [
      • Pais R.
      • Redheuil A.
      • Cluzel P.
      • Ratziu V.
      • Giral P.
      Relationship among fatty liver, specific and multiple-site atherosclerosis, and 10-year framingham score.
      ,
      • Lonardo A.
      • Nascimbeni F.
      • Mantovani A.
      • Targher G.
      Hypertension, diabetes, atherosclerosis and NASH: cause or consequence?.
      ,
      • Zhang L.
      • She Z.G.
      • Li H.
      • Zhang X.J.
      Non-alcoholic fatty liver disease: a metabolic burden promoting atherosclerosis.
      ]. Since there is still a lack of pharmacological treatments specific to NAFLD, whether treatments for NAFLD attenuate ASCVD remains unknown [
      • Cai J.
      • Zhang X.J.
      • Li H.
      Progress and challenges in the prevention and control of nonalcoholic fatty liver disease.
      ,
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ].
      Active investigations into the development of pharmacotherapeutics for NAFLD have been conducted in recent years [
      • Cai J.
      • Zhang X.J.
      • Li H.
      Progress and challenges in the prevention and control of nonalcoholic fatty liver disease.
      ,
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ]. However, several promising drug candidates, such as acetyl-coenzyme A carboxylase (ACC) inhibitors and farnesoid X receptor (FXR) agonists, failed in the final clinical trials due to potential side effects on the cardiovascular system [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ,
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ]. In this review, we first summarize the changes in lipid profiles and the mechanisms linking NAFLD to the progression of ASCVD. Importantly, we highlight the potential risks of/benefits to ASCVD conferred by NAFLD pharmaceutical treatments and discuss potential strategies and next-generation drugs for treating NASH without the unwanted side effects.

      2. NAFLD and lipid dysregulation

      The liver is a central organ of lipid metabolism. NAFLD and other metabolic syndromes alter insulin sensitivity in the periphery and viscera and affect the activity of enzymes that regulate lipid metabolism, thus dysregulating lipid homeostasis and distribution [
      • Bechmann L.P.
      • Hannivoort R.A.
      • Gerken G.
      • Hotamisligil G.S.
      • Trauner M.
      • et al.
      The interaction of hepatic lipid and glucose metabolism in liver diseases.
      ]. The dysregulation of lipid homeostasis in NAFLD manifests as increased hepatic lipid uptake and de novo lipogenesis (DNL), suppressed fatty acid oxidation (FAO), excessive very low-density lipoprotein (VLDL) production and secretion, and impaired high-density lipoprotein (HDL)-mediated cholesterol efflux [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ,
      • Deprince A.
      • Haas J.T.
      • Staels B.
      Dysregulated lipid metabolism links NAFLD to cardiovascular disease.
      ,
      • Ipsen D.H.
      • Lykkesfeldt J.
      • Tveden-Nyborg P.
      Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease.
      ] (Fig. 1).
      Fig. 1
      Fig. 1Overview of hepatic lipid metabolism in nonalcoholic fatty liver disease.
      Intrahepatic lipid levels are controlled by a balance between lipid acquisition and disposal, constituting four major pathways of hepatic lipid homeostasis. 1) hepatic lipid uptake, 2) de novo lipogenesis, 3) fatty acid oxidation, and 4) very low-density lipoprotein secretion. The liver acquires lipids through uptake of circulating fatty acids (from the adipose tissue lipolysis and the intestinal absorption of diet) and DNL. The two major fates of intrahepatic lipids are mitochondrial β-oxidation and esterification to form triglyceride. Triglycerides can be exported into the blood as very low-density lipoprotein. Consequently, lipid accumulation is the result of lipid acquisition pathways exceeding disposal pathways. ASCVD, atherosclerotic cardiovascular disease; NAFLD, nonalcoholic fatty liver disease; DNL, de novo lipogenesis; FAO, fatty acid oxidation; VLDL, very low-density lipoprotein; ATP, adenosine triphosphate; ER, endoplasmic reticulum.

      2.1 Increased adipose tissue lipolysis and dietary-derived fatty acids exacerbate hepatic lipid uptake

      Free fatty acids (FFAs) generated from lipolysis of peripheral adipose tissue are the main source of lipids in the liver. NAFLD patients with IR show increased lipolysis in peripheral adipose tissue, which may account for 60–70% of the accumulated fat in the liver [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • et al.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ]. Excessive lipolysis of peripheral adipose tissue is usually accompanied by adipose tissue inflammation and abnormal production of the hormones released by adipocytes, which further promotes IR and ectopic fat deposition [
      • Masoodi M.
      • Kuda O.
      • Rossmeisl M.
      • Flachs P.
      • Kopecky J.
      Lipid signaling in adipose tissue: connecting inflammation & metabolism.
      ,
      • Khan R.S.
      • Bril F.
      • Cusi K.
      • Newsome P.N.
      Modulation of insulin resistance in nonalcoholic fatty liver disease.
      ]. Of note, insulin plays an essential role in maintaining FFAs at an appropriate level by inhibiting lipolysis in peripheral adipose tissue. Lipolysis occurs when insulin sensitivity decreases, and a large amount of FFAs overflow into the circulation and shunt the liver [
      • Fuchs C.D.
      • Claudel T.
      • Trauner M.
      Role of metabolic lipases and lipolytic metabolites in the pathogenesis of NAFLD.
      ,
      • Luo P.
      • Wang P.X.
      • Li Z.Z.
      • Zhang X.J.
      • Jiang X.
      • et al.
      Hepatic oncostatin M receptor β regulates obesity-induced steatosis and insulin resistance.
      ] (Fig. 2).
      Fig. 2
      Fig. 2Hepatic lipid uptake and de novo lipogenesis activation in nonalcoholic fatty liver disease.
      Dietary fatty acids are mainly absorbed in the intestine and then transported to the liver. In nonalcoholic fatty liver disease, the lipolysis of adipose tissue is greatly enhanced. Moreover, hepatic De novo lipogenesis is mainly mediated by acetyl-Coenzyme A carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and lipogenic transcription factors, sterol regulatory element-binding protein-1c and carbohydrate response element-binding protein. Under conditions of chronic energy excess and hyperinsulinemia prevalent in nonalcoholic fatty liver disease, both lipogenic transcription factors and de novo lipogenesis are constantly active, which leads to elevated triglyceride synthesis. Regardless of their source, fatty acids are esterified into triglycerides and stored in intracellular lipid droplets. NAFLD, nonalcoholic fatty liver disease; DNL, de novo lipogenesis; ACC, acetyl-Coenzyme A carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; TG, triglyceride; SREBP, sterol regulatory element-binding protein; ChREBP, carbohydrate response element-binding protein.
      Dietary lipids are hydrolyzed by lipoprotein lipase (LPL) to form chylomicrons, which are primarily absorbed in the intestinal lumen. The FFAs produced by TG hydrolysis are absorbed from the intestine into the circulation and can be taken up by adipose tissue and liver [
      • Arab J.P.
      • Karpen S.J.
      • Dawson P.A.
      • Arrese M.
      • Trauner M.
      Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives.
      ]. In a healthy state, dietary fatty acids are mainly taken up by peripheral adipose tissue. However, in the IR state, LPL activity is suppressed, and the circulating TG level increases, which decreases the storage efficiency of dietary fatty acids in adipose tissue and increases the fat content in the liver [
      • Fielding B.
      Tracing the fate of dietary fatty acids: metabolic studies of postprandial lipaemia in human subjects.
      ] (Fig. 2).

      2.2 The activation of de novo lipogenesis

      The second-largest source of FFAs in the liver is DNL. In a healthy state, insulin directs excess carbohydrates to skeletal and muscle adipose tissue and promotes the storage of liver glucose as glycogen and DNL. However, IR hinders glucose oxidation and directs carbohydrates into the DNL pathway, leading to increased hepatic TG storage, glycogenesis, and DNL [
      • Friedman S.L.
      • Neuschwander-Tetri B.A.
      • Rinella M.
      • Sanyal A.J.
      Mechanisms of NAFLD development and therapeutic strategies.
      ,
      • Samuel V.T.
      • Shulman G.I.
      Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases.
      ]. Liver DNL is mainly mediated by ACC, fatty acid synthase (FASN), and sterol regulatory element-binding protein-1c [
      • Friedman S.L.
      • Neuschwander-Tetri B.A.
      • Rinella M.
      • Sanyal A.J.
      Mechanisms of NAFLD development and therapeutic strategies.
      ]. Excessive glucose in the liver is metabolized by glycolysis to produce pyruvic acid, which is subsequently converted to acetyl-CoA. ACC catalyzes the first critical stage of fatty acid synthesis, that is, the conversion of acetyl-CoA to malonyl-CoA, which can reduce fatty acid oxidation and further aggravate liver steatosis [
      • Bence K.K.
      • Birnbaum M.J.
      Metabolic drivers of non-alcoholic fatty liver disease.
      ]. Subsequently, malonyl-CoA is catalyzed by FASN and stearoyl-CoA desaturase 1 to form TGs, which are stored in hepatocytes [
      • Samuel V.T.
      • Shulman G.I.
      Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases.
      ]. At the same time, reduced malonyl-CoA levels repress the formation of polyunsaturated fatty acids (PUFAs), which subsequently enhance lipogenic gene expression and VLDL secretion [
      • Bence K.K.
      • Birnbaum M.J.
      Metabolic drivers of non-alcoholic fatty liver disease.
      ,
      • Zhang X.-J.
      • Ji Y.-X.
      • Cheng X.
      • Cheng Y.
      • Yang H.
      • et al.
      A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
      ,
      • Zhang X.-J.
      • She Z.-G.
      • Wang J.
      • Sun D.
      • Shen L.-J.
      • et al.
      Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.
      ] (Fig. 2).
      Sterol regulatory element-binding protein (SREBP)-1c and carbohydrate regulatory element-binding protein (ChREBP) are two key transcriptional regulators of DNL [
      • Sanders F.W.
      • Griffin J.L.
      De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.
      ]. SREBP-1c is activated by insulin and promotes the expression of adipogenesis genes such as FASN, ACC, and stearoyl-CoA desaturase 1 (SCD1) [
      • Kawano Y.
      • Cohen D.E.
      Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.
      ]. In this process, the mammalian target of rapamycin complex 1 (mTORC1) is required to stimulate adipogenesis [
      • Li S.
      • Brown M.S.
      • Goldstein J.L.
      Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis.
      ,
      • Yecies J.L.
      • Zhang H.H.
      • Menon S.
      • Liu S.
      • Yecies D.
      • et al.
      Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways.
      ]. mTORC1 enhances lipogenesis via the positive regulation of SREBPs [
      • Han J.
      • Wang Y.
      mTORC1 signaling in hepatic lipid metabolism.
      ]. ChREBP, in contrast to SREBP-1c, is activated by the postprandial rise in glucose delivery to hepatocytes [
      • Sanders F.W.
      • Griffin J.L.
      De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.
      ] and is required for normal lipogenesis [
      • Iizuka K.
      • Bruick R.K.
      • Liang G.
      • Horton J.D.
      • Uyeda K.
      Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.
      ]. ChREBP activity in adipose tissue has been proposed to be regulated by mTORC2, whereas mTORC2 regulates SREBP1 in the liver, suggesting that adipogenesis is regulated by mTORC2 in a tissue-specific manner [
      • Tang Y.
      • Wallace M.
      • Sanchez-Gurmaches J.
      • Hsiao W.Y.
      • Li H.
      • et al.
      Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism.
      ]. So far, only a few upstream regulators of mTORC2 have been found, and their regulatory mechanisms in hepatic steatosis have not been fully elucidated [
      • Zinzalla V.
      • Stracka D.
      • Oppliger W.
      • Hall M.N.
      Activation of mTORC2 by association with the ribosome.
      ,
      • Gan X.
      • Wang J.
      • Su B.
      • Wu D.
      Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate.
      ]. Notably, Bhat N et al. identified that phosphorylation and activation of mTORC2 are regulated by Dyrk1b, which directly activates mTORC2 to promote hepatic lipogenesis in mice [
      • Bhat N.
      • Narayanan A.
      • Fathzadeh M.
      • Kahn M.
      • Zhang D.
      • et al.
      Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice.
      ]. This not only sheds light on the pathogenesis of NASH but also provides new insights for the treatment of NASH.

      2.3 Reduced fatty acid oxidation

      Nonalcoholic fatty liver disease and IR increase fatty acid storage rather than fatty acid oxidation. The β-oxidation, carried out in mitochondria and peroxisomes, is the main route of most fatty acid oxidation [
      • Musso G.
      • Gambino R.
      • Cassader M.
      Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD).
      ]. In the case of excessive accumulation of lipids, α-oxidation and ω-oxidation in the endoplasmic reticulum can also be initiated [
      • Ipsen D.H.
      • Lykkesfeldt J.
      • Tveden-Nyborg P.
      Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease.
      ]. These oxidation processes produce a large amount of reactive oxygen species, which induce liver cell death and inflammation [
      • Rao M.S.
      • Reddy J.K.
      Peroxisomal beta-oxidation and steatohepatitis.
      ]. FAO is controlled by peroxisome proliferator-activated receptor (PPAR)-α, which is highly expressed in the liver. The activation of PPARα promotes FAO in mitochondria, peroxisomes, and cytochromes [
      • Kersten S.
      • Stienstra R.
      The role and regulation of the peroxisome proliferator activated receptor alpha in human liver.
      ]. Knockout of PPARα in mice results in decreased expression of genes regulating mitochondrial β-oxidation and increases fat content in the liver [
      • Montagner A.
      • Polizzi A.
      • Fouché E.
      • Ducheix S.
      • Lippi Y.
      • et al.
      Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD.
      ]. In patients with liver steatosis, the expression of PPARα is downregulated and negatively correlated with the severity of NASH [
      • Francque S.
      • Verrijken A.
      • Caron S.
      • Prawitt J.
      • Paumelle R.
      • et al.
      PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis.
      ]. Increased PPARα activity was positively associated with NASH amelioration in a longitudinal study [
      • Francque S.
      • Verrijken A.
      • Caron S.
      • Prawitt J.
      • Paumelle R.
      • et al.
      PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis.
      ] (Fig. 3).
      Fig. 3
      Fig. 3Hepatic fatty acid oxidation and very low-density lipoprotein secretion in nonalcoholic fatty liver disease.
      Fatty acids derived from lipolysis and from chylomicron remnants are taken up in the liver. A small fraction of intracellular fatty acid supply in the liver also comes from de novo lipogenesis in the cytosol. Fatty acyl-CoA might either mainly enter the mitochondrion for β-oxidation, or enter the cytosolic esterification pathway for triglyceride synthesis. The oxidation of fatty acids is controlled by peroxisome proliferator-activated receptor α, which is expressed at high levels in the liver. Furthermore, triglyceride can be packaged into very low-density lipoprotein particles together with apolipoprotein, cholesterol, and phospholipids. After the nascent very low-density lipoprotein particles are formed in the endoplasmic reticulum, the apolipoprotein B100 is lipidated with triglyceride under the catalysis of the microsomal triglyceride transfer protein. Then the very low-density lipoprotein particles are transported from the endoplasmic reticulum to the Golgi apparatus. During these processes, very low-density lipoprotein particles are further lipidated under the catalysis of MTP and finally enter the circulating plasma. NAFLD, nonalcoholic fatty liver disease; FAO, fatty acid oxidation; DNL, de novo lipogenesis; VLDL, very low-density lipoprotein; TG, triglyceride; PPARα, peroxisome proliferator-activated receptor α; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein.
      In addition to fatty acid oxidation, lipophagy is a novel form of autophagy that participates in the degradation of lipid droplets. Through the fusion of lipid droplets and lysosomes, TGs stored in lipid droplets are hydrolyzed and degraded [
      • Zechner R.
      • Madeo F.
      • Kratky D.
      Cytosolic lipolysis and lipophagy: two sides of the same coin.
      ]. Mechanism-mediated lipid degradation is also suppressed under metabolic stress and NAFLD.

      2.4 Increased very-low-density lipoprotein secretion

      The secretion of TG-rich VLDL particles from the liver is the only way to reduce liver lipid content [
      • Perry R.J.
      • Samuel V.T.
      • Petersen K.F.
      • Shulman G.I.
      The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes.
      ]. TGs are packaged together with apolipoproteins, cholesterol and phospholipids into water-soluble VLDL particles, which are subsequently secreted into the systemic circulation [
      • Fabbrini E.
      • Mohammed B.S.
      • Magkos F.
      • Korenblat K.M.
      • Patterson B.W.
      • et al.
      Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.
      ]. The assembly and secretion of VLDL particles involve a series of proteins and lipid factors. After the formation of nascent VLDL particles, apolipoprotein B100 (apoB100) is lipidated with TGs under the catalysis of microsomal triglyceride transfer protein (MTP). Then, the VLDL particles are transported from the endoplasmic reticulum to the Golgi apparatus and enter the circulating plasma [
      • Kawano Y.
      • Cohen D.E.
      Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.
      ] (Fig. 3). VLDL interacts with LPL and is converted to intermediate-density lipoprotein (IDL). Approximately half of IDL interacts with hepatic triglyceride lipase (HTL) to induce the loss of its TG content to form low-density lipoprotein (LDL). Patients with metabolic disorders have increased systematic oxidative stress, TG, and glucose levels. Circulating LDL can be further modified to generate oxidized LDL (ox-LDL), small dense LDL (sd-LDL), and glycated LDL, leading to atherosclerotic lesion formation.
      ApoB100 and MTP play important roles in the regulation of liver VLDL secretion. Patients with genetic defects of apolipoprotein B or MTP gene often suffer from hepatic steatosis secondary to impaired TG output [
      • Berriot-Varoqueaux N.
      • Aggerbeck L.P.
      • Samson-Bouma M.
      • Wetterau J.R.
      The role of the microsomal triglygeride transfer protein in abetalipoproteinemia.
      ,
      • Tanoli T.
      • Yue P.
      • Yablonskiy D.
      • Schonfeld G.
      Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.
      ]. Liver-specific knockout of MTP in mice results in moderate hepatic steatosis [
      • Raabe M.
      • Véniant M.M.
      • Sullivan M.A.
      • Zlot C.H.
      • Björkegren J.
      • et al.
      Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.
      ], and liver-specific overexpression of MTP can enhance VLDL secretion [
      • Tietge U.J.
      • Bakillah A.
      • Maugeais C.
      • Tsukamoto K.
      • Hussain M.
      • et al.
      Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B.
      ]. In addition, insulin can reduce liver VLDL production by inducing apoB100 degradation and inhibiting MTP synthesis, thereby reducing liver lipid output [
      • Kawano Y.
      • Cohen D.E.
      Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.
      ]. However, in the state of IR, insulin promotes DNL without inhibiting VLDL secretion [
      • Tessari P.
      • Coracina A.
      • Cosma A.
      • Tiengo A.
      Hepatic lipid metabolism and non-alcoholic fatty liver disease.
      ]. VLDL secretion is increased in NAFLD patients, and liver TG content is directly related to the secretion rate of VLDL-TG [
      • Fabbrini E.
      • Mohammed B.S.
      • Magkos F.
      • Korenblat K.M.
      • Patterson B.W.
      • et al.
      Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.
      ,
      • Adiels M.
      • Taskinen M.R.
      • Packard C.
      • Caslake M.J.
      • Soro-Paavonen A.
      • et al.
      Overproduction of large VLDL particles is driven by increased liver fat content in man.
      ]. Although the output of VLDL-TG in NAFLD patients increases with the increase of liver lipid content, the increased VLDL secretion cannot compensate for the overproduction of TG in the liver [
      • Fabbrini E.
      • Mohammed B.S.
      • Magkos F.
      • Korenblat K.M.
      • Patterson B.W.
      • et al.
      Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.
      ], thus, the liver TG concentration increases. Notably, mTORC1 is essential for this sustained VLDL-TG secretion and lipid homeostasis. mTORC1 hyperactivation in NAFLD enhances the expression of lipoprotein assembly (MTP and apoB) genes, thereby promoting the secretion of TG-rich VLDL particles [
      • Quinn 3rd, W.J.
      • Wan M.
      • Shewale S.V.
      • Gelfer R.
      • Rader D.J.
      • et al.
      mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.
      ,
      • Roberts J.L.
      • He B.
      • Erickson A.
      • Moreau R.
      Improvement of mTORC1-driven overproduction of apoB-containing triacylglyceride-rich lipoproteins by short-chain fatty acids, 4-phenylbutyric acid and (R)-α-lipoic acid, in human hepatocellular carcinoma cells.
      ].

      2.5 Impaired HDL-mediated cholesterol efflux

      Low levels of high-density lipoprotein (HDL)-cholesterol are one of the risk factors for ASCVD [
      • Fon Tacer K.
      • Rozman D.
      Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation.
      ]. HDL exerts anti-atherosclerotic properties by inhibiting inflammatory, oxidative and apoptotic pathways [
      • Talbot C.P.J.
      • Plat J.
      • Ritsch A.
      • Mensink R.P.
      Determinants of cholesterol efflux capacity in humans.
      ], mainly because it promotes cholesterol efflux in macrophages [
      • Tall A.R.
      Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.
      ]. Cholesterol efflux is the first step in reverse cholesterol transport, whereby cholesterol is cleared from macrophages by high-density lipoprotein, transported to the liver for metabolism, and finally secreted into bile [
      • Tall A.R.
      Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.
      ]. Multiple studies have demonstrated an inverse relationship between HDL-mediated cholesterol efflux capacity (CEC) and CVD risk independent of HDL-cholesterol, whereas after adjusting for CEC, the inverse relationship between HDL-cholesterol and CVD risk disappeared. These results suggest improving CEC is a better target for reducing CVD risk [
      • Talbot C.P.J.
      • Plat J.
      • Ritsch A.
      • Mensink R.P.
      Determinants of cholesterol efflux capacity in humans.
      ,
      • Khera A.V.
      • Cuchel M.
      • de la Llera-Moya M.
      • Rodrigues A.
      • Burke M.F.
      • et al.
      Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
      ,
      • Rohatgi A.
      • Khera A.
      • Berry J.D.
      • Givens E.G.
      • Ayers C.R.
      • et al.
      HDL cholesterol efflux capacity and incident cardiovascular events.
      ]. Furthermore, clinical studies have shown that HDL-mediated CEC is inhibited in NAFLD patients, which may increase the risk of atherosclerosis in NAFLD patients [
      • van den Berg E.H.
      • Gruppen E.G.
      • Ebtehaj S.
      • Bakker S.J.L.
      • Tietge U.J.F.
      • et al.
      Cholesterol efflux capacity is impaired in subjects with an elevated Fatty Liver Index, a proxy of non-alcoholic fatty liver disease.
      ,
      • Fadaei R.
      • Poustchi H.
      • Meshkani R.
      • Moradi N.
      • Golmohammadi T.
      • et al.
      Impaired HDL cholesterol efflux capacity in patients with non-alcoholic fatty liver disease is associated with subclinical atherosclerosis.
      ].

      3. Pharmacotherapy for NAFLD and risk of ASCVD

      Numerous lines of evidence have suggested a strong correlation between NAFLD and ASCVD [
      • Zhou J.
      • Bai L.
      • Zhang X.J.
      • Li H.
      • Cai J.
      Nonalcoholic fatty liver disease and cardiac remodeling risk: pathophysiological mechanisms and clinical implications.
      ,
      • Cai J.
      • Zhang X.J.
      • Ji Y.X.
      • Zhang P.
      • She Z.G.
      • et al.
      Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases.
      ]. The accumulated lipid burden in NAFLD patients significantly increases the risk of atherosclerosis [
      • Chatrath H.
      • Vuppalanchi R.
      • Chalasani N.
      Dyslipidemia in patients with nonalcoholic fatty liver disease.
      ]. Recently, novel reagents have shown encouraging treatment effects in attenuating NAFLD in clinical trials. However, many of these effects are accompanied by changes in circulating lipid profiles, which may cause potential risks of/benefits to ASCVD (Table 1 and Fig. 4).
      Table 1Pharmacotherapy for NAFLD and risk of ASCVD.
      Therapeutic targetsAgentsClinicalTrials.gov numberPhaseStudy populationStudy typeDurationEffect on NALFDEffects on lipids
      ACC inhibitors
      NDI-010976//Obese and Overweightrandomized, double-blind, placebo-controlled, crossover trial10 hoursdecreases hepatic DNL/
      GS-0976NCT028565552Hepatic steatosisrandomized, placebo-controlled trial12 weeksdecreases hepatic steatosis, selected markers of fibrosis, and liver biochemistryhypertriglyceridemia
      MK-4074NCT01431521/NAFLDdouble-blind, randomized, placebo- and active-controlled parallel group study4 weeksreduces hepatic steatosishypertriglyceridemia; increase VLDL and LDL
      PF-05221304NCT032488822aNAFLDrandomized, double-blind, placebo-controlled, dose-ranging, parallel-group study16 weeksreduces hepatic fathypertriglyceridemia; increase ApoC3
      PF-05221304 co-administered with PF-06865571NCT037761752aNAFLDrandomized, double-blind, placebo-controlled, 2 × 2 factorial, four-arm parallel-group study6 weeksreduces hepatic fatmitigate ACC inhibitor-mediated hypertriglyceridemia
      FXR agonists
      Obeticholic acidNCT012654982NASHmulticentre, double-blind, placebo-controlled, parallel group, randomised clinical trial72 weeksimprove the histological features of NASHincrease TC and LDL-C; decrease HDL-C
      Obeticholic acidNCT025483513NASHmulticentre, randomised, double-blind, placebo-controlled study18 monthsimprove fibrosis and key components of NASH disease activityincrease TC and LDL-C; decrease HDL-C
      TropifexorNCT028551642NASHrandomized, double blind, placebo-controlled, 3-part, adaptive-design study48 weeksdecrease hepatic fat fractionincrease LDL-C
      CilofexorNCT028546052NASHdouble-blind, placebo-controlled trial24 weeksdecrease hepatic steatosisno significant alteration in serum lipid profile
      CilofexorNCT029434602Primary sclerosing cholangitismulticenter, double‐blind, randomized, placebo‐controlled trial12 weeksreduce ALP, GGT, ALT, AST and pro‐fibrogenic cytokine TIMP‐1decrease HDL-C
      MET409//NASHrandomized, placebo-controlled study12 weeksreduce hepatic fatincrease LDL-C
      GLP-1 receptor agonists
      LiraglutideNCT012371192NASHmulticentre, double-blinded, randomised, placebo-controlled trial48 weeksimprove steatohepatitis without worsening fibrosisdecrease LDL-C; increase HDL-C
      ExenatideNCT02303730/T2DM patients with NAFLDopen-label, randomized, controlled, parallel-group, multicentre trial24 weeksreduce hepatic fatdecrease LDL-C
      CotadutideNCT032350502bOverweight/obesity with T2DMrandomized, parallel-group, double-blind, placebo-controlled study54 weeksreduce NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) indexdecrease TG
      TirzepatideNCT031316872bT2DMrandomised, double-blind study26 weeksdecrease NASH-related biomarkersdecrease TG and TC
      TirzepatideNCT038829703T2DMrandomised, open-label, parallel-group, phase 3 SURPASS-3 trial52 weeksreduces liver fat contentdecrease TG and VLDL-C; increase HDL-C
      SemaglutideNCT029709422NASHrandomized, double-blind, placebo-controlled, parallel-group trial72 weeksimprove liver fibrosiswithout lipid profile changes
      PPAR agonists
      PioglitazoneNCT009946824NASH with prediabetes or T2DMrandomized, double-blind, placebo-controlled trial18 monthsimprove liver histology score and reduce hepatic fatdecrease TG and increase HDL-C
      MSDC-0602KNCT027844442bNASHrandomized, double-blind, placebo-controlled study52 weeksfail to improve liver histology/
      PirfenidoneNCT040994072Advanced liver fibrosisreal-life, multicenter, open-label, proof-of-concept trial12 monthsameliorate fibrosis/
      ElafibranorNCT016948492NASHinternational, multicenter, randomized placebo-controlled study52 weeksrelieve nonalcoholic steatohepatitis without worsening fibrosisdecrease TG and LDL-C; increase HDL-C
      SaroglitazarNCT030617212NAFLD/NASHmulticenter, randomized, double-blind, placebo-controlled study16 weeksreduce hepatic fat and ALTdecrease TG and VLDL
      LanifibranorNCT030080702bNoncirrhotic, highly active NASHdouble-blind, randomized, placebo-controlled trial24 weeksdecrease SAF-A score and improve fibrosisdecrease TC, TG and ApoB
      ACLY inhibitors
      Bempedoic AcidNCT016072942Patients with T2DM and elevated LDL-Csingle-center, double-blind, placebo-controlled trial4 weeks/decrease LDL-C and TC
      Bempedoic AcidNCT026666643ASCVD, hypercholesterolemia, or bothrandomized, double-blind, placebo-controlled, parallel-group trial52 weeks/decrease LDL-C, TC and ApoB
      FASN inhibitors
      TVB-2640NCT039382462aNASHrandomized, multicenter placebo-controlled, single-blinded clinical study12 weeksreduce hepatic fat and improve fibrotic biomarkersdecrease TC and LDL-C
      THR-β agonists
      ResmetiromNCT029122602NASHdouble-blind, randomized, placebo-controlled study36 weeksreduce hepatic fatreduce LDL-C, TG, ApoB and ApoC3
      VK2809NCT029271842aNAFLDrandomized, double-Blind, placebo-controlled, multicenter Study12 weeksreduce hepatic fat/
      FGF analogs
      PegbelferminNCT024133722aNASHmulticenter, randomized, double-blind, placebo-controlled, parallel-group study16 weeksreduce hepatic fatreduce LDL and TG; increase HDL
      EfruxiferminNCT039764012aNASHmulticenter, randomized, double-blind, placebo-controlled, parallel-group study16 weeksreduce hepatic fat fractionreduce LDL-C, TC, ApoB and ApoC3; increase HDL-C
      AldaferminNCT024431162NASHmulticenter, international, randomized, double-blind, placebo-controlled trial12 weeksreduce hepatic fatreduce TG; increase LDL-C
      SCD1 inhibitors
      AramcholNCT010941582NAFLDmulticenter, randomized, double-blind, and placebo-controlled trial3 monthsreduce hepatic fatwithout lipid profile changes
      AramcholNCT022795242bNASHmulticenter, randomized, double-blind, placebo-controlled study52 weeksreduce hepatic fatwithout lipid profile changes
      SGLT2 inhibitors
      EmpagliflozinNCT031183363T2DMrandomized, parallel-group, double-blind trial12 weeksreduce hepatic fatreduce TG; increase HDL-C
      EmpagliflozinNCT026379734T2DMrandomized, parallel-group, double-blind trial24 weeksreduce hepatic fatwithout lipid profile changes
      DapagliflozinNCT022794072Participants with T2DM and NAFLDmulticentre, randomised, placebo-controlled, double-blind, parallel-group trial12 weeksreduce hepatic fatincrease ApoC3
      IpragliflozinUMIN000022651/Patients with T2DM and NAFLDrandomized, open-label, multicenter, active-controlled trial24 weeksameliorate hepatic steatosisreduce TG; increase HDL-C
      CanagliflozinNCT020094881T2DMdouble-blind, parallel-group, placebo-controlled trial24 weeksreduce hepatic triglyceride content/
      TofogliflozinjRCTs031180159/NAFLD patients with T2DMopen-label, prospective, single-center, randomized study24 weeksreduce hepatic fatwithout lipid profile changes
      LuseogliflozinUMIN000016090/Patients with T2DM and NAFLDsingle-centre, prospective, randomized, open-label, controlled study6 monthsreduce hepatic fat/
      ASCVD, atherosclerotic cardiovascular disease; NAFLD, non-alcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes; DNL, de novo lipogenesis; ACC, acetyl-Coenzyme A carboxylase; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very low density lipoprotein; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma‐glutamyl transferase; TIMP‐1, tissue inhibitor of metalloproteinase 1; SAF-A score, the activity part of the Steatosis, Activity, Fibrosis scoring system; GLP-1, glucagon-like peptide-1; PPAR, peroxisome proliferator-activated receptor; ACLY, ATP-citrate lyase; apolipoprotein B, ApoB; apolipoprotein C3, ApoC3; ACC, acetyl-Coenzyme A carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; FXR, farnesoid X receptor; THR, thyroid hormone receptor; FGF, fibroblast growth factor; SGLT2, sodium-glucose cotransporter 2.
      Fig. 4
      Fig. 4Pharmacotherapy for nonalcoholic fatty liver disease and risk of atherosclerotic cardiovascular disease.
      The development and progression of nonalcoholic fatty liver disease involves complex pathogenesis, which permits the development of a wide array of potentially viable therapeutic targets. This figure is a concise summary of the main effects of various nonalcoholic fatty liver disease pharmacotherapy and potential atherosclerotic cardiovascular disease risks, with more detailed description of the individual agents and clinical studies provided in later text. ASCVD, atherosclerotic cardiovascular disease; NEFA, nonesterified fatty acid; GLP-1, glucagon-like peptide-1; PPAR, peroxisome proliferator-activated receptor; ACLY, ATP-citrate lyase; ACC, acetyl-Coenzyme A carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; FXR, farnesoid X receptor; THR, thyroid hormone receptor; TCA, tricarboxylic acid; VLDL, very low-density lipoprotein; TG, triglyceride; PUFA, polyunsaturated fatty acids; DGAT, diacylglycerol acyltransferase; DAG, diacylglycerol; APOC, apolipoprotein C.

      3.1 Reagents that disrupt the circulating lipid profile, which may increase the risk of ASCVD

      3.1.1 Acetyl-CoA carboxylase inhibitors

      Acetyl-CoA carboxylase has a crucial role in fatty acid metabolism and has two major isoforms, namely, ACC1 and ACC2 [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ]. ACC1 catalyzes the first critical stage of fatty acid biosynthesis, the conversion of acetyl-CoA to malonyl-CoA [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ]. ACC2 inhibits carnitine palmitoyltransferase 1 (CPT1) to regulate FAO in mitochondria [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ]. Therefore, inhibition of ACC seems to be a potential therapy for NAFLD by inhibiting DNL and promoting FAO production in the liver [
      • Alkhouri N.
      • Lawitz E.
      • Noureddin M.
      • DeFronzo R.
      • Shulman G.I.
      GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH).
      ]. GS-0976 (also known as NDI-010976) and MK-4074 are two potent ACC1 and 2 inhibitors developed for treating NASH. In multiple clinical trials, GS-0976 and MK-4074 demonstrated a predominant effect in reducing liver lipid content by repressing DNL and increasing FAO [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ,
      • Stiede K.
      • Miao W.
      • Blanchette H.S.
      • Beysen C.
      • Harriman G.
      • et al.
      Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study.
      ,
      • Loomba R.
      • Kayali Z.
      • Noureddin M.
      • Ruane P.
      • Lawitz E.J.
      • et al.
      GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.
      ]. The ACC inhibitors exhibited a profound dose-dependent inhibition of hepatic DNL even with single-dose treatment. The reduction in hepatic steatosis was correlated with the doses of ACC inhibitors and length of treatment [
      • Calle R.A.
      • Amin N.B.
      • Carvajal-Gonzalez S.
      • Ross T.T.
      • Bergman A.
      • et al.
      ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.
      ].
      Unfortunately, hypertriglyceridemia is frequently observed during treatment with these ACC1/2 inhibitors [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ,
      • Loomba R.
      • Kayali Z.
      • Noureddin M.
      • Ruane P.
      • Lawitz E.J.
      • et al.
      GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.
      ,
      • Calle R.A.
      • Amin N.B.
      • Carvajal-Gonzalez S.
      • Ross T.T.
      • Bergman A.
      • et al.
      ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.
      ]. The definitive mechanism of hypertriglyceridemia induced by ACC inhibitors has not yet been fully elucidated. It may be due to the sharp reduction in malonyl-CoA, which can cause a decrease in the production of PUFAs, increasing the expression of SREBP-1c in a compensatory manner and resulting in increased lipogenesis in hepatocytes and export of VLDL and TG into the peripheral [
      • Alkhouri N.
      • Lawitz E.
      • Noureddin M.
      • DeFronzo R.
      • Shulman G.I.
      GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH).
      ]. In addition, lower PUFA decreases the expression of PPARα, which increases the expressions of apolipoprotein C3 (apoC3), increases serum apoC3 levels, and diminishes lipoprotein lipase activity, thereby inhibiting lipid degradation in plasma [
      • Goedeke L.
      • Bates J.
      • Vatner D.F.
      • Perry R.J.
      • Wang T.
      • et al.
      Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents.
      ,
      • Morze J.
      • Koch M.
      • Aroner S.A.
      • Budoff M.
      • McClelland R.L.
      • et al.
      Associations of HDL subspecies defined by ApoC3 with non-alcoholic fatty liver disease: the multi-ethnic study of atherosclerosis.
      ]. Although this asymptomatic hypertriglyceridemia may resolve spontaneously in some patients [
      • Loomba R.
      • Kayali Z.
      • Noureddin M.
      • Ruane P.
      • Lawitz E.J.
      • et al.
      GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.
      ], dysregulated lipid profile could increase the risk of ASCVD in the long run. The detrimental effect on lipid profile has been a major obstacle to the successful initiation of clinical application of ACC inhibitors. Possible approaches to address this obstacle include suppressing compensatory increases in lipogenic genes [
      • Calle R.A.
      • Amin N.B.
      • Carvajal-Gonzalez S.
      • Ross T.T.
      • Bergman A.
      • et al.
      ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.
      ], enhancing hepatic lipid oxidation or lipid degradation in plasma [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ], or fine-tuning ACC activity using moderate ACC inhibitors [
      • Zhang X.-J.
      • Ji Y.-X.
      • Cheng X.
      • Cheng Y.
      • Yang H.
      • et al.
      A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
      ]. A phase 2a clinical study administered combined treatment with ACC inhibitors and diacylglycerol acyltransferase 2 (DGAT2) inhibitors to NAFLD patients [
      • Calle R.A.
      • Amin N.B.
      • Carvajal-Gonzalez S.
      • Ross T.T.
      • Bergman A.
      • et al.
      ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.
      ]. DGAT2 inhibitors lead to the downregulation of SREBP-1, thereby inhibiting the expression of lipogenic genes and the induction of oxidative pathways [
      • Yu X.X.
      • Murray S.F.
      • Pandey S.K.
      • Booten S.L.
      • Bao D.
      • et al.
      Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.
      ]. Coadministration of a DGAT2 inhibitor effectively mitigated ACC inhibitor-induced hypertriglyceridemia and normalized lipogenesis-related gene expressions [
      • Calle R.A.
      • Amin N.B.
      • Carvajal-Gonzalez S.
      • Ross T.T.
      • Bergman A.
      • et al.
      ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.
      ]. ACC inhibitor-mediated hypertriglyceridemia may also be associated with PUFA deficiency and reduced PPARα expression levels. PPARα agonists, along with PUFA supplementation, have also been shown to normalize ACC inhibitor-induced hypertriglyceridemia [
      • Kim C.W.
      • Addy C.
      • Kusunoki J.
      • Anderson N.N.
      • Deja S.
      • et al.
      Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.
      ]. Moreover, ACC inhibition-mediated hypertriglyceridemia may also be due to the high potency of ACC inhibitor [
      • Loomba R.
      • Kayali Z.
      • Noureddin M.
      • Ruane P.
      • Lawitz E.J.
      • et al.
      GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.
      ] or the inhibitory effect on both ACC1 and ACC2. It has been demonstrated that the use of low-dose ACC inhibitors may ameliorate ACC inhibitor-induced hypertriglyceridemia [
      • Loomba R.
      • Kayali Z.
      • Noureddin M.
      • Ruane P.
      • Lawitz E.J.
      • et al.
      GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.
      ], however, it is challenging to balance efficacy and side effects to establish an effective therapeutic window. IMA-1, a small molecule, ameliorates hepatic steatosis by blocking the arachidonate 12-lipoxygenase (ALOX12) mediated ACC1 lysosomal degradation pathways and does not elicit hyperlipidemia in either mice or macaques [
      • Zhang X.-J.
      • Ji Y.-X.
      • Cheng X.
      • Cheng Y.
      • Yang H.
      • et al.
      A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.
      ,
      • Zhang X.-J.
      • She Z.-G.
      • Wang J.
      • Sun D.
      • Shen L.-J.
      • et al.
      Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.
      ]. Since IMA-1 specifically blocks the interaction between ALOX12 and ACC1, even high doses of IMA-1 only partially reduce the expression of ACC1 without causing a significant decrease in PUFA content, which is considered one of the leading causes of ACC inhibitor-induced hypertriglyceridemia. The efficacy and safety data of this new monotherapy strategy urgently require further clinical trials to evaluate.

      3.1.2 Farnesoid X receptor agonists

      Farnesoid X receptor is a nuclear receptor mainly expressed in the liver and intestine [
      • Clifford B.L.
      • Sedgeman L.R.
      • Williams K.J.
      • Morand P.
      • Cheng A.
      • et al.
      FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
      ]. Activation of FXR reduces intestinal lipid absorption and inhibits lipogenesis in the liver, ultimately reducing hepatic steatosis [
      • Clifford B.L.
      • Sedgeman L.R.
      • Williams K.J.
      • Morand P.
      • Cheng A.
      • et al.
      FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
      ]. Furthermore, FXR activation exerts multiple beneficial metabolic effects, including promoting FAO in the liver, regulating gluconeogenesis, and restoring insulin sensitivity [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ,
      • Anstee Q.M.
      • Reeves H.L.
      • Kotsiliti E.
      • Govaere O.
      • Heikenwalder M.
      From NASH to HCC: current concepts and future challenges.
      ]. Lower FXR expression levels were observed in the livers of fatty liver patients, and FXR expression levels were inversely correlated with fatty liver severity [
      • Min H.K.
      • Kapoor A.
      • Fuchs M.
      • Mirshahi F.
      • Zhou H.
      • et al.
      Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.
      ]. Similarly, FXR deficiency in mice leads to hepatic steatosis and inflammation [
      • Kong B.
      • Luyendyk J.P.
      • Tawfik O.
      • Guo G.L.
      Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet.
      ]. Therefore, FXR agonists may be a potential strategy for the treatment of NAFLD.
      Obeticholic acid, a common FXR agonist, was shown in the FLINT phase 2 trial to significantly improve NAFLD activity scores (NASs) and mean fibrosis stage in NASH patients [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ]. In the subsequent REGENERATE phase 3 clinical trial, interim analysis results showed that an 18-month treatment with obeticholic acid significantly improved fibrosis, although the expected endpoint of NASH regression was not achieved [
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • Rinella M.
      • Anstee Q.M.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ]. However, increased circulating LDL and decreased HDL levels are frequently observed during obeticholic acid treatment [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ,
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • Rinella M.
      • Anstee Q.M.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ]. Activation of FXR inhibits the conversion of cholesterol to bile acids, resulting in decreased bile acid synthesis, which may be responsible for the elevated circulating LDL levels caused by obeticholic acid [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ]. Furthermore, FXR activation can also regulate reverse cholesterol transport [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ]. Given these complexities, investigators need to be vigilant about the effects of obeticholic acid on cholesterol metabolism, as elevated LDL levels increase ASCVD risk, which may counteract the therapeutic effect of NAFLD [
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • Sanderson S.O.
      • Lindor K.D.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      ]. Given that obeticholic acid promotes the development of a proatherosclerotic lipid profile in NASH patients [
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      ,
      • Younossi Z.M.
      • Ratziu V.
      • Loomba R.
      • Rinella M.
      • Anstee Q.M.
      • et al.
      Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
      ], combining obeticholic acid with atorvastatin was evaluated in the CONTROL phase 2 study. The results showed that the combination treatment with atorvastatin reduced LDL-cholesterol levels below baseline, although the plasma lipid profile deteriorated after 4 weeks of obeticholic acid administration [
      • Pockros P.J.
      • Fuchs M.
      • Freilich B.
      • Schiff E.
      • Kohli A.
      • et al.
      CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.
      ].
      In addition to obeticholic acid, several FXR agonists have been investigated in clinical trials. Tropifexor, a nonsteroidal FXR agonist, demonstrated anti-inflammatory and antisteatogenic effects in the FLIGHT-FXR phase 2 trial, but alterations in the serum lipid profile (increased LDL-cholesterol levels and decreased HDL-cholesterol levels) were also observed during treatment [
      • Sanyal A.
      • Lopez P.
      • Lawitz E.
      • Kim W.
      • Huang J.-F.
      • et al.
      SAT-357-Tropifexor, a farnesoid X receptor agonist for the treatment of non-alcoholic steatohepatitis: interim results based on baseline body mass index from first two parts of Phase 2b study FLIGHT-FXR.
      ,
      • Lucas K.J.
      • Lopez P.
      • Lawitz E.
      • Sheikh A.
      • Aizenberg D.
      • et al.
      Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results.
      ]. Cilofexor, a nonsteroidal FXR agonist, demonstrated an antisteatotic effect in a clinical study. Unlike tropifexor, only pruritus was observed in the cilofexor-treated group, with no significant alteration in the serum lipid profile [
      • Patel K.
      • Harrison S.A.
      • Elkhashab M.
      • Trotter J.F.
      • Herring R.
      • et al.
      Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial.
      ]. This may be due to the limited oral bioavailability of cilofexor and the lack of enterohepatic circulation, causing only a transient increase in plasma fibroblast growth factor (FGF) 19 and thereby suppressing FGF19-induced hypercholesterolemia [
      • Patel K.
      • Harrison S.A.
      • Elkhashab M.
      • Trotter J.F.
      • Herring R.
      • et al.
      Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial.
      ]. In another phase 2 trial, although patients treated with cilofexor did not experience increases in total cholesterol (TC) or LDL-cholesterol levels, HDL-cholesterol levels were reduced by approximately 10% [
      • Lucas K.J.
      • Lopez P.
      • Lawitz E.
      • Sheikh A.
      • Aizenberg D.
      • et al.
      Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results.
      ]. The association of reduced HDL-cholesterol levels with cardiovascular risk warrants further evaluation [
      • Trauner M.
      • Gulamhusein A.
      • Hameed B.
      • Caldwell S.
      • Shiffman M.L.
      • et al.
      The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis.
      ]. MET409, a structurally optimized novel FXR agonist, was shown in a clinical study to significantly reduce liver fat content with less effect on serum lipid profiles (a 9% placebo-adjusted LDL-cholesterol increase) [
      • Harrison S.A.
      • Bashir M.R.
      • Lee K.J.
      • Shim-Lopez J.
      • Lee J.
      • et al.
      A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.
      ]. This suggests that the adverse effects of FXR agonists on serum lipid profiles can be ameliorated by structural optimization. Taken together, the future of FXR agonists in the treatment of NAFLD is likely to combine therapy with other drugs or structural optimization to allow lower doses, thereby reducing the risk of atherosclerosis.

      3.2 Reagents that favor circulating lipid profiles that may alleviate the risk of ASCVD

      3.2.1 Glucagon-like peptide-1 agonists

      Glucagon-like peptide-1 (GLP-1) is a peptide hormone that improves glucose metabolism by increasing insulin secretion and inhibiting glucagon production, thereby reducing hepatic nonesterified fatty acid (NEFA) overload caused by TG lipolysis [
      • Armstrong M.J.
      • Hull D.
      • Guo K.
      • Barton D.
      • Hazlehurst J.M.
      • et al.
      Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
      ]. In addition, GLP-1 also has beneficial effects in reducing appetite and body weight [
      • Armstrong M.J.
      • Hull D.
      • Guo K.
      • Barton D.
      • Hazlehurst J.M.
      • et al.
      Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
      ,
      • Jinnouchi H.
      • Sugiyama S.
      • Yoshida A.
      • Hieshima K.
      • Kurinami N.
      • et al.
      Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus.
      ]. These effects are appropriate for NAFLD patients, who are often overweight and have IR. Therefore, GLP-1 receptor agonists are a viable treatment option for NAFLD.
      Liraglutide is a long-acting GLP-1 receptor agonist suitable for the treatment of patients with type 2 diabetes mellitus (T2DM). In the 48-week LEAN phase 2 clinical trial, liraglutide demonstrated beneficial effects on liver histology in patients with NASH, significantly improving steatohepatitis without worsening fibrosis [
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • Barton D.
      • Hull D.
      • et al.
      Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ]. Notably, patients receiving liraglutide experienced significantly reduced body weight and LDL-cholesterol levels and increased HDL levels, and the mechanism by which liraglutide ameliorated NASH may be due to the improvement of liver metabolic dysfunction and IR [
      • Armstrong M.J.
      • Hull D.
      • Guo K.
      • Barton D.
      • Hazlehurst J.M.
      • et al.
      Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
      ,
      • Armstrong M.J.
      • Gaunt P.
      • Aithal G.P.
      • Barton D.
      • Hull D.
      • et al.
      Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
      ]. Exenatide is another GLP-1 receptor agonist used in the clinical treatment of diabetic patients. A multicenter clinical trial showed that exenatide reduced hepatic steatosis, body weight, and plasma LDL-cholesterol levels in T2DM patients with NAFLD [
      • Liu L.
      • Yan H.
      • Xia M.
      • Zhao L.
      • Lv M.
      • et al.
      ]. Cotadutide is a dual receptor agonist of GLP-1 and glucagon. In a phase 2 clinical study, treatment with cotadutide for 54 weeks significantly reduced liver fibrosis and serum TG levels in participants with overweight/obesity and T2DM [
      • Nahra R.
      • Wang T.
      • Gadde K.M.
      • Oscarsson J.
      • Stumvoll M.
      • et al.
      Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study.
      ]. In addition, semaglutide, a next-generation GLP-1 agonist, improved steatohepatitis in NASH patients without changes to the lipid profile [
      • Newsome P.N.
      • Buchholtz K.
      • Cusi K.
      • Linder M.
      • Okanoue T.
      • et al.
      A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.
      ]. Tirzepatide (also known as LY3298176), a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, has been shown to significantly decrease NASH-related biomarkers, body weight, and the levels of serum TGs and TC in a phase 2 clinical study with T2DM patients [
      • Hartman M.L.
      • Sanyal A.J.
      • Loomba R.
      • Wilson J.M.
      • Nikooienejad A.
      • et al.
      Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes.
      ,
      • Frias J.P.
      • Nauck M.A.
      • Van J.
      • Kutner M.E.
      • Cui X.
      • et al.
      Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.
      ]. In the SURPASS-2 trial, improvements in lipid profile and liver-enzyme levels were observed in T2DM patients treated with tirzepatide [
      • Frías J.P.
      • Davies M.J.
      • Rosenstock J.
      • Pérez Manghi F.C.
      • Fernández Landó L.
      • et al.
      Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes.
      ]. Notably, in the latest SURPASS-3 trial, 52 weeks of tirzepatide treatment significantly improved hepatic steatosis and reduced serum TGs and VLDL-cholesterol levels [
      • Gastaldelli A.
      • Cusi K.
      • Fernández Landó L.
      • Bray R.
      • Brouwers B.
      • et al.
      Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial.
      ]. All these results suggest that tirzepatide is a viable strategy for the treatment of NASH, which will be further explored in a subsequent clinical study (NCT04166773). The beneficial effects of GLP-1 agonists on NASH may result from a combination of effects involving improved IR, decreased body weight and blood glucose, and direct beneficial effects on the liver. Preclinical studies have demonstrated that GLP-1 agonists may reduce hepatic inflammation through mechanisms that are at least in part independent of body weight reduction [
      • Rakipovski G.
      • Rolin B.
      • Nøhr J.
      • Klewe I.
      • Frederiksen K.S.
      • et al.
      The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE(-/-) and LDLr(-/-) mice by a mechanism that includes inflammatory pathways.
      ]. Although GLP-1 agonists are only authorized to treat T2DM, these GLP-1 agonists have potential as NAFLD drugs with few side effects due to their beneficial effects of reducing body weight and improving lipid profiles, which can greatly reduce the risk of ASCVD. Furthermore, GLP-1 agonists have also been shown to improve endothelial dysfunction and suppress inflammation, which may contribute to a reduction in ASCVD risk [
      • Ma X.
      • Liu Z.
      • Ilyas I.
      • Little P.J.
      • Kamato D.
      • et al.
      GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential.
      ]. Taken together, GLP-1 agonists have great potential not only in the treatment of NAFLD, but also in reducing the risk of ASCVD, providing a rationale for precision therapy with GLP-1 agonists in appropriate target patient classes.

      3.2.2 Peroxisome proliferator-activated receptor agonists

      Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that mainly include the following three subtypes: PPARα, PPARδ, and PPARγ [
      • Tyagi S.
      • Gupta P.
      • Saini A.S.
      • Kaushal C.
      • Sharma S.
      The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
      ]. PPAR-α is highly expressed in the liver, and its activation promotes FAO and protects hepatocytes from oxidative stress-induced damage. Furthermore, in vivo and in vitro studies have shown that activation of PPAR-α reduces TG levels associated with metabolic syndrome [
      • Tyagi S.
      • Gupta P.
      • Saini A.S.
      • Kaushal C.
      • Sharma S.
      The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
      ]. PPARγ is highly expressed in adipose tissue and pancreas. Activation of PPARγ enhances adipocyte differentiation and storage capacity, insulin sensitivity, and FAO levels in the liver [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ,
      • Tyagi S.
      • Gupta P.
      • Saini A.S.
      • Kaushal C.
      • Sharma S.
      The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
      ,
      • Tong J.
      • Han C.J.
      • Zhang J.Z.
      • He W.Z.
      • Zhao G.J.
      • et al.
      Hepatic interferon regulatory factor 6 alleviates liver steatosis and metabolic disorder by transcriptionally suppressing peroxisome proliferator-activated receptor γ in mice.
      ]. PPARδ is ubiquitously present throughout the whole body and has essential roles in inhibiting enhanced NEFA oxidation and lipogenesis as well as anti-inflammatory effects [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ,
      • Tyagi S.
      • Gupta P.
      • Saini A.S.
      • Kaushal C.
      • Sharma S.
      The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
      ]. Based on the abovementioned mechanism, PPAR agonists have great potential in the treatment of NAFLD.
      Pioglitazone, a PPARγ agonist, is a first-generation thiazolidinedione [
      • Cusi K.
      • Orsak B.
      • Bril F.
      • Lomonaco R.
      • Hecht J.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ]. In a phase 4 clinical study, 58% of NASH patients with diabetes mellitus in the pioglitazone group achieved the primary outcome after 18 months of pioglitazone treatment. Pioglitazone significantly improved hepatic steatosis, inflammation and swelling, decreased TG levels, and increased HDL-cholesterol levels [
      • Cusi K.
      • Orsak B.
      • Bril F.
      • Lomonaco R.
      • Hecht J.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      ]. To reduce side effects, researchers have developed second-generation PPARγ agonists. However, MSDC-0602K, a second-generation PPARγ agonist, failed to improve liver histology in NASH patients in a 52-week phase 2b trial, and there was no monitoring of lipid profiles [
      • Harrison S.A.
      • Alkhouri N.
      • Davison B.A.
      • Sanyal A.
      • Edwards C.
      • et al.
      Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study.
      ]. Pirfenidone is a PPARα agonist that inhibits adipogenesis and fibrosis [
      • Sandoval-Rodriguez A.
      • Monroy-Ramirez H.C.
      • Meza-Rios A.
      • Garcia-Bañuelos J.
      • Vera-Cruz J.
      • et al.
      Pirfenidone is an agonistic ligand for PPARα and improves NASH by activation of SIRT1/LKB1/pAMPK.
      ]. In the PROMETEO phase 2 study, 12 months of pirfenidone treatment improved fibrosis in more than a third of patients, but the effect on serum lipids was not monitored [
      • Poo J.L.
      • Torre A.
      • Aguilar-Ramírez J.R.
      • Cruz M.
      • Mejía-Cuán L.
      • et al.
      Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study.
      ]. The impact of pirfenidone on lipid profiles needs to be addressed in further clinical studies. Notably, PPARα activation has been shown to improve atherosclerotic dyslipidemia, inhibit vascular inflammation and macrophage foam cell formation, thereby inhibiting the progression of atherosclerosis [
      • Yu X.H.
      • Zheng X.L.
      • Tang C.K.
      Peroxisome proliferator-activated receptor α in lipid metabolism and atherosclerosis.
      ]. Based on the multiple benefits of PPAR agonists, this suggests a potential therapeutic value in NAFLD and ASCVD.
      Agonists that act simultaneously on two or three PPAR subtypes appear to be more potent in controlling metabolic disorders than reagents acting on a single PPAR subtype. Elafibranor, a dual agonist of PPARα and PPARδ, significantly improved the histological features of NASH in a Phase 2 clinical trial enrolling patients with NASH [
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • Bedossa P.
      • Lehert P.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      ]. More notably, elafibranor also improved lipid parameters, such as lowering TG and LDL-cholesterol levels and raising HDL-cholesterol levels [
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • Bedossa P.
      • Lehert P.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      ]. Saroglitazar is also a dual agonist that activates PPARα and PPARγ. In a recent phase 2 clinical trial involving NAFLD/NASH patients, saroglitazar was shown to improve hepatic steatosis, IR, and atherogenic dyslipidemia [
      • Gawrieh S.
      • Noureddin M.
      • Loo N.
      • Mohseni R.
      • Awasty V.
      • et al.
      Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial.
      ]. Lanifibranor is a pan-PPAR agonist that activates PPARα, PPARδ, and PPARγ. In a recently completed phase 2b clinical study involving patients with NASH, lanifibranor was also shown to significantly reduce the activity of steatohepatitis and improve liver fibrosis. In addition, lanifibranor reduced liver enzyme levels and improved most biomarkers of lipids (reduced TC, TG, and apoB levels), inflammation, and fibrosis [
      • Francque S.M.
      • Bedossa P.
      • Ratziu V.
      • Anstee Q.M.
      • Bugianesi E.
      • et al.
      A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH.
      ]. In summary, based on the beneficial effects of PPAR agonists in regulating lipid metabolism, they not only have promising potential for the treatment of NAFLD but also reduce the risk of ASCVD exacerbated by lipid metabolism disorders.

      3.2.3 ATP-citrate lyase inhibitors

      ATP-citrate lyase (ACLY) is an important enzyme that links carbohydrates to lipid metabolism, catalyzing the conversion of citric acid to oxaloacetate and acetyl-CoA and ultimately promoting the biosynthesis of fatty acids and cholesterol [
      • Feng X.
      • Zhang L.
      • Xu S.
      • Shen A.Z.
      ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review.
      ]. Liver samples from NAFLD patients exhibit increased ACLY expression, which may contribute to NAFLD progression [
      • Guo L.
      • Guo Y.Y.
      • Li B.Y.
      • Peng W.Q.
      • Chang X.X.
      • et al.
      Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease.
      ]. Consistently, hepatic ACLY deficiency in mice ameliorates hepatic steatosis by inhibiting DNL and improves glucose metabolism by enhancing insulin sensitivity in skeletal muscle [
      • Feng X.
      • Zhang L.
      • Xu S.
      • Shen A.Z.
      ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review.
      ,
      • Wang Q.
      • Jiang L.
      • Wang J.
      • Li S.
      • Yu Y.
      • et al.
      Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice.
      ]. These studies suggest that ACLY is a potential strategy for the treatment of NAFLD.
      Bempedoic acid, an ACLY inhibitor, is a prodrug that is converted to the active form (bempedoic acid-CoA) only in the liver. In addition to inhibiting the conversion of citrate to acetyl-CoA, bempedoic acid-CoA can also reduce ACC activity, thereby inhibiting the conversion of acetyl-CoA to malonyl-CoA, and ultimately inhibiting fatty acid synthesis [
      • Feng X.
      • Zhang L.
      • Xu S.
      • Shen A.Z.
      ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review.
      ]. More notably, bempedoic acid also increases circulating LDL clearance by enhancing hepatic LDL receptor expression [
      • Feng X.
      • Zhang L.
      • Xu S.
      • Shen A.Z.
      ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review.
      ]. Consistent with these mechanisms, bempedoic acid has been shown to reduce circulating atherogenic lipoprotein levels and hepatic TG and TC levels in a NASH animal model [
      • Sanjay K.V.
      • Vishwakarma S.
      • Zope B.R.
      • Mane V.S.
      • Mohire S.
      • et al.
      ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score.
      ]. Multiple phase 2 and 3 clinical trials on bempedoic acid have also shown that bempedoic acid reduces TC, apoB, and LDL-cholesterol levels [
      • Cicero A.F.G.
      • Fogacci F.
      • Hernandez A.V.
      • Banach M.
      • Lipid
      • et al.
      Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: a systematic review and meta-analysis.
      ]. Bempedoic acid is expected to be a promising treatment for NAFLD and reduce the risk of ASCVD.

      3.2.4 Fatty acid synthase inhibitors

      Fatty acid synthase catalyzes hepatic DNL and is a key enzyme regulating hepatic lipid metabolism [
      • Hu Y.
      • He W.
      • Huang Y.
      • Xiang H.
      • Guo J.
      • et al.
      Fatty acid synthase–suppressor screening identifies sorting nexin 8 as a therapeutic target for NAFLD.
      ]. Studies have demonstrated that FASN expression is significantly elevated in the liver of NAFLD or obesity [
      • Dorn C.
      • Riener M.O.
      • Kirovski G.
      • Saugspier M.
      • Steib K.
      • et al.
      Expression of fatty acid synthase in nonalcoholic fatty liver disease.
      ,
      • Eissing L.
      • Scherer T.
      • Tödter K.
      • Knippschild U.
      • Greve J.W.
      • et al.
      De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health.
      ]. Inhibition of FASN improved hepatic steatosis by inhibiting hepatic fatty acid synthesis [
      • Hu Y.
      • He W.
      • Huang Y.
      • Xiang H.
      • Guo J.
      • et al.
      Fatty acid synthase–suppressor screening identifies sorting nexin 8 as a therapeutic target for NAFLD.
      ,
      • Wu M.
      • Singh S.B.
      • Wang J.
      • Chung C.C.
      • Salituro G.
      • et al.
      Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes.
      ,
      • Syed-Abdul M.M.
      • Parks E.J.
      • Gaballah A.H.
      • Bingham K.
      • Hammoud G.M.
      • et al.
      Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de novo Lipogenesis in Males With Metabolic Abnormalities.
      ]. TVB-2640 is a reversible FASN inhibitor that has been shown to reduce hepatic DNL and hepatic TG levels in subjects in a small clinical study. Interestingly, unlike the effect of ACC inhibitors, the plasma TG level was unchanged, whereas TC and LDL-cholesterol levels were significantly reduced in subjects who received 100 mg/d TVB-2640 [
      • Syed-Abdul M.M.
      • Parks E.J.
      • Gaballah A.H.
      • Bingham K.
      • Hammoud G.M.
      • et al.
      Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de novo Lipogenesis in Males With Metabolic Abnormalities.
      ]. More importantly, the 12-week FASCINATE-1 phase 2a study showed that TVB-2640 significantly improved hepatic steatosis and reduced TC, LDL-cholesterol and HDL-cholesterol levels in NASH patients. Baseline ratios of TC/HDL cholesterol did not change after treatment, suggesting that the HDL-cholesterol decrease resulted from decreased TC levels [
      • Loomba R.
      • Mohseni R.
      • Lucas K.J.
      • Gutierrez J.A.
      • Perry R.G.
      • et al.
      TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial.
      ]. In addition, 12 weeks of TVB-2640 treatment did not cause an increase in plasma TG levels, suggesting that long-term TVB-2640 treatment may reduce ASCVD risk [
      • Loomba R.
      • Mohseni R.
      • Lucas K.J.
      • Gutierrez J.A.
      • Perry R.G.
      • et al.
      TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial.
      ]. Taken together, FASN inhibitors have promising potential in the treatment of NASH. Notably, increased malonyl-CoA resulting from FASN inhibition impairs physiological and pathological angiogenesis through mTOR signaling [
      • Bruning U.
      • Morales-Rodriguez F.
      • Kalucka J.
      • Goveia J.
      • Taverna F.
      • et al.
      Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation.
      ]. The safety and efficacy of FASN inhibitors need to be evaluated in further clinical trials.

      3.2.5 Thyroid hormone receptor-β agonists

      Thyroid hormone regulates DNL, fatty acid oxidation, and cholesterol metabolism [
      • Sinha R.A.
      • Bruinstroop E.
      • Singh B.K.
      • Yen P.M.
      Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists.
      ]. There are two subtypes of thyroid hormone receptors: thyroid hormone receptor α (THR-α) and thyroid hormone receptor β (THR-β). THR-α is mainly expressed in the heart and skeletal muscle and regulates cardiovascular functions. THR-β is mainly expressed in the liver, and its activation enhances fatty acid oxidation and promotes hepatic cholesterol metabolism [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ,
      • Finan B.
      • Parlee S.D.
      • Yang B.
      Nuclear hormone and peptide hormone therapeutics for NAFLD and NASH.
      ]. Furthermore, thyroid hormone is not suitable for long-term treatment of metabolic diseases due to the increased number of adverse effects on the heart and bones mediated by THR-α [
      • Chen Z.
      • Yu Y.
      • Cai J.
      • Li H.
      Emerging molecular targets for treatment of nonalcoholic fatty liver disease.
      ]. Therefore, THR-β agonists are currently being developed to maximize the treatment of NAFLD and minimize side effects mediated by THR-α.
      Resmetirom (MGL-3196) is a highly selective THR-β agonist that has been shown to reduce hepatic cholesterol and TG levels in a rodent model of NAFLD [
      • Kelly M.J.
      • Pietranico-Cole S.
      • Larigan J.D.
      • Haynes N.E.
      • Reynolds C.H.
      • et al.
      Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia.
      ]. A phase 2 clinical trial showed that resmetirom treatment significantly improved hepatic steatosis and fibrosis activity markers in patients with biopsy‐confirmed NASH [
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • Zhou R.
      • Moylan C.A.
      • et al.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Harrison S.A.
      • Bashir M.
      • Moussa S.E.
      • McCarty K.
      • Pablo Frias J.
      • et al.
      Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH.
      ]. Furthermore, resmetirom treatment also reduced LDL-cholesterol, TG, apoB, and apoC3 levels, which may reduce ASCVD risk in NASH patients [
      • Harrison S.A.
      • Bashir M.R.
      • Guy C.D.
      • Zhou R.
      • Moylan C.A.
      • et al.
      Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ]. VK2809, also a selective THR-β agonist, was evaluated in a phase 2a clinical study. The results of this study demonstrated that low-dose VK2809 (5 mg) treatment significantly improved hepatic steatosis in NAFLD patients [
      • Loomba R.
      • Neutel J.
      • Mohseni R.
      • Bernard D.
      • Severance R.
      • et al.
      LBP-20-VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat with both low and high doses in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled trial.
      ]. These data suggest that THR-β agonists improve NAFLD and lipid profiles and provide a strong rationale for further developing low-dose THR-β agonist therapy for the treatment of NAFLD.

      3.3 Ambiguous ASCVD risk

      3.3.1 Fibroblast growth factor analogs

      Fibroblast growth factor 21 is a hormone that plays a key role in regulating glucose and lipid metabolism. Circulating level of FGF21 is elevated in metabolically compromised states, such as obesity, T2DM, and NAFLD [
      • Zarei M.
      • Pizarro-Delgado J.
      • Barroso E.
      • Palomer X.
      • Vázquez-Carrera M.
      Targeting FGF21 for the treatment of nonalcoholic steatohepatitis.
      ]. Indeed, FGF21 deficiency promotes hepatic steatosis, inflammation, and fibrosis, and FGF21 analogs ameliorate NASH by inhibiting these pathological processes [
      • Zarei M.
      • Pizarro-Delgado J.
      • Barroso E.
      • Palomer X.
      • Vázquez-Carrera M.
      Targeting FGF21 for the treatment of nonalcoholic steatohepatitis.
      ]. Pegbelfermin, a PEGylated FGF21 analog, has been shown in a Phase 2a clinical trial to significantly improve hepatic steatosis in patients with NASH [
      • Sanyal A.
      • Charles E.D.
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Harrison S.A.
      • et al.
      Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.
      ]. Pegbelfermin was also observed to decrease LDL and TG levels and increase HDL levels, and this improvement in the lipid profile may be due to increased adiponectin levels [
      • Sanyal A.
      • Charles E.D.
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Harrison S.A.
      • et al.
      Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.
      ]. Efruxifermin is a long-acting FGF21 analog for the treatment of NASH. In the 16-week phase 2a BALANCED clinical trial, efruxifermin significantly reduced the liver fat fraction and was found to reduce TG, LDL-cholesterol, apoB, and apoC3 levels [
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • Neff G.
      • Patil R.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      ]. The decrease in circulating TG levels may be due to a reduction in apolipoprotein [
      • Harrison S.A.
      • Ruane P.J.
      • Freilich B.L.
      • Neff G.
      • Patil R.
      • et al.
      Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.
      ]. Overall, the amelioration of dyslipidemia suggests that the improvement in dyslipidemia suggests that FGF21 analogs may reduce the risk of ASCVD in NASH patients.
      Fibroblast growth factor 19 is a gastrointestinal hormone that plays a key role in the regulation of bile acid and glucose homeostasis. Aldafermin (NGM282) is an engineered analog of FGF19 under investigation to treat NAFLD. In a phase 2 study, aldafermin rapidly and significantly improved liver steatosis in NASH patients. However, unlike FGF21 analogs, aldafermin treatment reduced TG levels but increased LDL-cholesterol levels [
      • Harrison S.A.
      • Rinella M.E.
      • Abdelmalek M.F.
      • Trotter J.F.
      • Paredes A.H.
      • et al.
      NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ]. In subsequent safety and efficacy studies, 24 weeks of aldafermin treatment also increased TC and LDL-cholesterol levels [
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ]. Elevated LDL levels may be attributed to, similar to FGF19, NGM282 potently inhibiting CYP7A1 expression via the FGFR4-β Klotho receptor complex, thereby inhibiting cholesterol efflux and ultimately resulting in reduced LDL-cholesterol clearance [
      • Harrison S.A.
      • Rinella M.E.
      • Abdelmalek M.F.
      • Trotter J.F.
      • Paredes A.H.
      • et al.
      NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ]. The effect of aldafermin on ASCVD risk requires close attention in further clinical studies, although the combination with a statin could compensate for the detrimental effect of aldafermin on lipid profiles [
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      ].

      3.3.2 Stearoyl-CoA desaturase 1 inhibitors

      Stearoyl-CoA desaturase 1 is a key enzyme in hepatic lipogenesis that converts saturated fatty acids into monounsaturated fatty acids. SCD1 inhibition decreases the synthesis and increases β-oxidation of fatty acids, resulting in decreased hepatic storage of TGs [
      • Safadi R.
      • Konikoff F.M.
      • Mahamid M.
      • Zelber-Sagi S.
      • Halpern M.
      • et al.
      The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease.
      ]. Aramchol, a liver-targeted SCD-1 inhibitor, partially inhibits hepatic SCD1 protein expression and reduces hepatic TG levels and fibrosis in animal models of steatohepatitis or fibrosis [
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • Poordad F.
      • Fuster F.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ]. In a phase 2 study, administration of aramchol for 3 months significantly reduced liver fat content in patients with NAFLD without changes in the lipid profile [
      • Safadi R.
      • Konikoff F.M.
      • Mahamid M.
      • Zelber-Sagi S.
      • Halpern M.
      • et al.
      The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease.
      ]. In a subsequent 52-week phase 2b clinical study, hepatic fat was reduced in the aramchol 400-mg arm, and no changes in lipid profiles were observed [
      • Ratziu V.
      • de Guevara L.
      • Safadi R.
      • Poordad F.
      • Fuster F.
      • et al.
      Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.
      ]. However, in preclinical studies, the effect of SCD1 inhibition on atherosclerosis risk appears controversial. Although SCD1 inhibition is largely protective against diet-induced hepatic steatosis and hypertriglyceridemia, it may also exacerbate atherosclerosis by promoting inflammatory cytokine secretion [
      • Brown J.M.
      • Chung S.
      • Sawyer J.K.
      • Degirolamo C.
      • Alger H.M.
      • et al.
      Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis.
      ]. ASCVD risk and lipid profile changes should be assessed in this ongoing international phase 3 trial (NCT04104321).

      3.3.3 Sodium-glucose cotransporter 2 inhibitors

      Sodium-glucose cotransporter 2 (SGLT2) is a transporter mainly expressed in the kidney and is involved in the reabsorption of most glucose in primary urine [
      • Liu Z.
      • Ma X.
      • Ilyas I.
      • Zheng X.
      • Luo S.
      • et al.
      Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics.
      ]. Inhibition of SGLT2 increases urinary glucose excretion by inhibiting glucose reabsorption, thereby reducing plasma glucose levels and body weight [
      • Vallon V.
      The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.
      ]. SGLT2 inhibitors, a novel oral hypoglycemic agent, have attracted increasing attention for NAFLD treatment [
      • Mantovani A.
      • Byrne C.D.
      • Targher G.
      Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review.
      ,
      • Zhang Y.
      • Liu X.
      • Zhang H.
      • Wang X.
      Efficacy and safety of empagliflozin on nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      ]. In preclinical studies on rodent models, SGLT2 inhibitors significantly reduce body weight while improving hepatic steatosis and fibrosis [
      • Qiang S.
      • Nakatsu Y.
      • Seno Y.
      • Fujishiro M.
      • Sakoda H.
      • et al.
      Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus.
      ,
      • Nasiri-Ansari N.
      • Nikolopoulou C.
      • Papoutsi K.
      • Kyrou I.
      • Mantzoros C.S.
      • et al.
      Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE((-/-)) mice by activating autophagy and reducing ER stress and apoptosis.
      ]. Nevertheless, multiple clinical studies have revealed that SGLT-2 inhibitors decrease TG levels, increase HDL-cholesterol levels, and increase LDL-cholesterol levels, which may lead to ambiguous cardiovascular risk [
      • Ptaszynska A.
      • Hardy E.
      • Johnsson E.
      • Parikh S.
      • List J.
      Effects of dapagliflozin on cardiovascular risk factors.
      ,
      • Lim S.
      • Eckel R.H.
      • Koh K.K.
      Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors.
      ].
      Empagliflozin, an SGLT-2 inhibitor, ameliorated hepatic steatosis in patients with T2DM [
      • Kuchay M.S.
      • Krishan S.
      • Mishra S.K.
      • Farooqui K.J.
      • Singh M.K.
      • et al.
      Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial).
      ]. In a phase 3 study, empagliflozin treatment for 12 weeks effectively reduced liver fat and was found to exert beneficial effects on TG and HDL-cholesterol levels in T2DM [
      • Gaborit B.
      • Ancel P.
      • Abdullah A.E.
      • Maurice F.
      • Abdesselam I.
      • et al.
      Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.
      ]. However, in a phase 4 study over 24 weeks, empagliflozin reduced liver fat without changes in blood lipids in patients with T2DM [
      • Kahl S.
      • Gancheva S.
      • Strassburger K.
      • Herder C.
      • Machann J.
      • et al.
      Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: a randomized, double-blind, phase 4, placebo-controlled trial.
      ]. Notably, in a phase 3 clinical study involving T2DM patients, a slight increase in LDL-cholesterol levels was observed in the empagliflozin-treated group [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ]. This increase may be partly due to hemoconcentration, as SGLT2 inhibitors reduce blood volume following an increase in urine output [
      • Lim S.
      • Eckel R.H.
      • Koh K.K.
      Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors.
      ]. In addition, it may also be related to the mechanism by which SGLT2 inhibitors reduce the catabolism of LDL [
      • Briand F.
      • Mayoux E.
      • Brousseau E.
      • Burr N.
      • Urbain I.
      • et al.
      Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism.
      ].
      Dapagliflozin is another SGLT2 inhibitor used in the clinical treatment of diabetic patients. In the EFFECT-II study, dapagliflozin treatment for 12 weeks improved hepatic steatosis in overweight individuals [
      • Eriksson J.W.
      • Lundkvist P.
      • Jansson P.A.
      • Johansson L.
      • Kvarnström M.
      • et al.
      Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
      ]. Notably, treatment of dapagliflozin induced a significant increase in apolipoprotein C3 levels without significant changes in LDL-cholesterol and HDL-cholesterol and TG levels [
      • Eriksson J.W.
      • Lundkvist P.
      • Jansson P.A.
      • Johansson L.
      • Kvarnström M.
      • et al.
      Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
      ]. Ipragliflozin is also an SGLT2 inhibitor suitable for the treatment of patients with T2DM. In a multicenter trial, treatment of ipragliflozin for 24 weeks improved hepatic steatosis, decreased TG, and increased HDL-cholesterol levels [
      • Ito D.
      • Shimizu S.
      • Inoue K.
      • Saito D.
      • Yanagisawa M.
      • et al.
      Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial.
      ]. Similarly, in a small clinical trial involving patients with T2DM, significant reductions in LDL-cholesterol levels were found in the ipragliflozin-treated group [
      • Bando Y.
      • Tohyama H.
      • Aoki K.
      • Kanehara H.
      • Hisada A.
      • et al.
      Ipragliflozin lowers small, dense low-density lipoprotein cholesterol levels in Japanese patients with type 2 diabetes mellitus.
      ]. Other SGLT2 inhibitors, such as canagliflozin, tofogliflozin, and luseogliflozin, have been shown to improve hepatic steatosis and fibrosis without affecting blood lipid levels in multiple clinical trials [
      • Cusi K.
      • Bril F.
      • Barb D.
      • Polidori D.
      • Sha S.
      • et al.
      Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes.
      ,
      • Yoneda M.
      • Honda Y.
      • Ogawa Y.
      • Kessoku T.
      • Kobayashi T.
      • et al.
      Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial.
      ,
      • Shibuya T.
      • Fushimi N.
      • Kawai M.
      • Yoshida Y.
      • Hachiya H.
      • et al.
      Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study.
      ]. Although SGLT2 inhibitors have been found to improve NAFLD and reduce body weight, the lipid profile changes induced by SGLT2 inhibitors need to be closely watched in further clinical studies.

      4. Conclusion and perspectives

      Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. Due to rapid economic growth and lifestyle changes, the prevalence of NAFLD has risen dramatically over the past two decades and has emerged as a driver of ASCVD. This article summarizes the mechanisms of lipid disturbance in NAFLD, highlighting the potential risk of/benefit to ASCVD conferred by NAFLD drug therapy.
      In recent years, the development of and research on drug treatments for NAFLD have been more active than ever. A series of therapeutic targets have been identified, and some of these compounds can improve NAFLD-associated proatherosclerotic lipid profiles while treating NAFLD, such as GLP-1 receptor agonists, PPAR agonists, ACLY inhibitors, FASN inhibitors, and THR-β agonists. Worryingly, however, the worsened lipid profile caused by ACC inhibitors and FXR agonists, as well as the uncertain impact of FGF analogs, SCD1 inhibitors, and SGLT-2 inhibitors on lipid profiles, necessitates rigorous cardiovascular risk assessment in subsequent drug development and clinical trials. Therefore, evaluating the potential association of NAFLD with ASCVD and the potential risk of/benefit to ASCVD conferred by NAFLD drug therapy will help clinicians personalize treatment plans and minimize overall cardiovascular risk in patients with NAFLD.

      Financial support

      This work was supported by grants from the National Science Foundation of China ( 81770053 , 81970364 , 81870171 , 82170436 ), and the Hubei Province Innovation Platform Construction Project ( 20204201117303072238 ).

      Author contributions

      All authors contributed to the writing of this manuscript and approved the final version.

      Declaration of interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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