Research Article| Volume 375, P21-29, June 2023

Hepatic Cdkal1 deletion regulates HDL catabolism and promotes reverse cholesterol transport

  • Author Footnotes
    1 These two authors contributed equally to this work.
    Dan Bi An
    1 These two authors contributed equally to this work.
    Yonsei University Graduate School, Seoul, South Korea
    Search for articles by this author
  • Author Footnotes
    1 These two authors contributed equally to this work.
    Soo-jin Ann
    1 These two authors contributed equally to this work.
    Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, South Korea
    Search for articles by this author
  • Seungmin Seok
    Yonsei University Graduate School, Seoul, South Korea
    Search for articles by this author
  • Yura Kang
    Department of Biostatistics and Computing, Yonsei University Graduate School, Seoul, South Korea
    Search for articles by this author
  • Sang-Hak Lee
    Corresponding author. Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, South Korea.
    Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea

    Pohang University of Science and Technology (POSTECH), Pohang, South Korea
    Search for articles by this author
  • Author Footnotes
    1 These two authors contributed equally to this work.


      • Liver-specific Cdkal1 deficient mice showed higher CEC and RCT with less tendency of atherosclerosis.
      • This study verified the effect of CDKAL1 found in our previous human genetic data.
      • Downregulation of EL and HL and upregulation of SR-B1 indicated altered HDL catabolism mediators.
      • Cholesterol concentrations were higher in the large HDL subclass in these mice.
      • CDKAL1 and related molecules could be therapeutic targets against vascular pathology.


      Background and aims

      Associations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL) metabolism, atherosclerosis, and related pathways.


      Lipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre:Cdkal1fl/fl and Cdkal1fl/fl mice. Aortic atherosclerosis was compared in Apoe−/−Alb-Cre:Cdkal1fl/fl and Apoe−/− mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre:Cdkal1fl/fl mice were examined.


      HDL-cholesterol level tended to be higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice, irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre:Cdkal1fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe−/−Alb-Cre:Cdkal1fl/fl mice than in the Apoe−/− mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre:Cdkal1fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007).


      The promotion of CEC and RCT in Alb-Cre:Cdkal1fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism. This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Yang Y.
        • Han K.
        • Park S.H.
        • Kim M.K.
        • Yoon K.-H.
        • et al.
        High-density lipoprotein cholesterol and the risk of myocardial infarction, stroke, and cause-specific mortality: a nationwide cohort study in Korea.
        J Lipid Atheroscler. 2021; 10: 74-87
        • Cho Y.K.
        • Jung C.H.
        HDL-C and cardiovascular risk: you don't need to worry about extremely high HDL-C levels.
        J Lipid Atheroscler. 2021; 10: 57-61
        • Holmes M.V.
        • Asselbergs F.W.
        • Palmer T.M.
        • Drenos F.
        • Lanktree M.B.
        • et al.
        Mendelian randomization of blood lipids for coronary heart disease.
        Eur. Heart J. 2015; 36: 539-550
        • Schwartz G.G.
        • Olsson A.G.
        • Abt M.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effects of dalcetrapib in patients with a recent acute coronary syndrome.
        N. Engl. J. Med. 2012; 367: 2089-2099
        • Zhao Q.
        • Wang J.
        • Miao Z.
        • Zhang N.R.
        • Hennessey S.
        • et al.
        A Mendelian randomization study of the role of lipoprotein subfractions in coronary artery disease.
        Elife. 2021; 10e58361
        • George R.T.
        • Abuhatzira L.
        • Stoughton S.M.
        • Karathanasis S.K.
        • She D.
        • et al.
        MEDI6012: recombinant human lecithin cholesterol acyltransferase, high-density lipoprotein, and low-density lipoprotein receptor-mediated reverse cholesterol transport.
        J. Am. Heart Assoc. 2021; 10e014572
        • Kingwell B.A.
        • Nicholls S.
        • Velkoska E.
        • Didichenko S.A.
        • Duffy D.
        • et al.
        Antiatherosclerotic effects of CSL112 mediated by enhanced cholesterol efflux capacity.
        J. Am. Heart Assoc. 2022; 11e024754
        • Cheon E.J.
        • Cha D.H.
        • Cho S.K.
        • Noh H.-M.
        • Park S.
        • et al.
        Novel association between CDKAL1 and cholesterol efflux capacity: replication after GWAS-based discovery.
        Atherosclerosis. 2018; 273: 21-27
        • Lee H.A.
        • Park H.
        • Hong Y.S.
        Sex differences in the effects of CDKAL1 variants on glycemic control in diabetic patients: findings from the Korean genome and epidemiology study.
        Diabetes Metab. J. 2022; Online ahead of print
        • Wei F.Y.
        • Suzuki T.
        • Watanabe S.
        • Kimura S.
        • Kaitsuka T.
        • et al.
        Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice.
        J. Clin. Invest. 2011; 121: 3598-3608
        • Oldoni F.
        • Sinke R.J.
        • Kuivenhoven J.A.
        Mendelian disorders of high-density lipoprotein metabolism.
        Circ. Res. 2014; 114: 124-142
        • Palmisano B.T.
        • Zhu L.
        • Stafford J.M.
        Role of estrogens in the regulation of liver lipid metabolism.
        Adv. Exp. Med. Biol. 2017; 1043: 227-256
        • 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.
        N. Engl. J. Med. 2011; 364: 127-135
        • Borja M.S.
        • Ng K.F.
        • Irwin A.
        • Hong J.
        • Wu X.
        • et al.
        HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity.
        J. Lipid Res. 2015; 56: 2002-2009
        • Choi S.Y.
        • Hirata K.
        • Ishida T.
        • Quertermous T.
        • Cooper A.D.
        Endothelial lipase: a new lipase on the block.
        J. Lipid Res. 2002; 43: 1763-1769
        • Yasuda T.
        • Ishida T.
        • Rader D.J.
        Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis.
        Circ. J. 2010; 74: 2263-2270
        • Brown R.J.
        • Lagor W.R.
        • Sankaranaravana S.
        • Yasuda T.
        • Quertermous T.
        • et al.
        Impact of combined deficiency of hepatic lipase and endothelial lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins.
        Circ. Res. 2010; 107: 357-364
        • Escolà -Gil J.C.
        • Chen X.
        • Julve J.
        • Quesada H.
        • Santos D.
        • et al.
        Hepatic lipase- and endothelial lipase-deficiency in mice promotes macrophage-to-feces RCT and HDL antioxidant properties.
        Biochim. Biophys. Acta. 2013; 1831: 691-697
        • Schilcher I.
        • Kern S.
        • Hrzenjak A.
        • Eichmann T.O.
        • Stojakovic T.
        • et al.
        Impact of endothelial lipase on cholesterol efflux capacity of serum and high-density lipoprotein.
        Sci. Rep. 2017; 712485
        • Takiguchi S.
        • Ayaori M.
        • Yakushiji E.
        • Nishida T.
        • Nakaya K.
        • et al.
        Hepatic overexpression of endothelial lipase lowers high-density lipoprotein but maintains reverse cholesterol transport in mice: role of scavenger receptor class B type I/ATP-binding cassette transporter A1-dependent pathways.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 1454-1467
        • Le Lay J.E.
        • Du Q.
        • Mehta M.B.
        • Bhagroo N.
        • Hummer B.T.
        • et al.
        Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial.
        Sci. Transl. Med. 2021; 13 (eabb0602)
        • Ruff C.T.
        • Koren M.J.
        • Grimsby J.
        • Rosenbaum A.I.
        • Tu X.
        • et al.
        LEGACY: phase 2a trial to evaluate the safety, pharmacokinetics, and pharamacodynamic effects of the anti-EL (endothelial lipase) antibody MEDI5884 in patients with stable coronary artery disease.
        Arterioscler. Thromb. Vasc. Biol. 2021; 41: 3005-3014
        • Low-Kam C.
        • Rhainds D.
        • Lo K.S.
        • Barhdadi A.
        • Boulé M.
        • et al.
        Variants at the ApoE/C1/C2/C4 locus modulate cholesterol efflux capacity independently of high-density lipoprotein cholesterol.
        J. Am. Heart Assoc. 2018; 7e009545
        • Chujo T.
        • Tomizawa K.
        Human transfer RNA modopathies: disease caused by aberrations in transfer RNA modifications.
        FEBS J. 2021; 288: 7096-7122
        • Ishida T.
        • Choi S.Y.
        • Kundu R.K.
        • Spin J.
        • Yamashita T.
        • et al.
        Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice.
        J. Biol. Chem. 2004; 279: 45085-45092
        • Ko K.W.
        • Paul A.
        • Ma K.
        • Li L.
        • Chan L.
        Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE–/– and LDLR–/– mice.
        J. Lipid Res. 2005; 46: 2586-2594
        • Wang C.
        • Nishijima K.
        • Kitajima S.
        • Niimi M.
        • Yan H.
        • et al.
        Increased hepatic expression of endothelial lipase inhibits cholesterol diet–induced hypercholesterolemia and atherosclerosis in transgenic rabbits.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1282-1289
        • Yu X.
        • Lu J.
        • Li J.
        • Guan W.
        • Deng S.
        • et al.
        Serum triglyceride lipase concentrations are independent risk factors for coronary artery disease and in-stent restenosis.
        J. Atherosclerosis Thromb. 2019; 26: 762-774
        • Cole J.
        • Blackhurst D.M.
        • Solomon G.A.E.
        • Ratanjee B.D.
        • Benjamin R.
        • et al.
        Atherosclerotic cardiovascular disease in hyperalphalipoproteinemia due to LIPG variants.
        J Clin Lipidol. 2021; 15: 142-150.e2
        • Annema W.
        • Tietge U.J.
        Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport.
        Curr. Atherosclerosis Rep. 2011; 13: 257-265
        • Rosenson R.S.
        • Brewer Jr., H.B.
        • Davidson W.S.
        • Fayad Z.A.
        • Fuster V.
        • et al.
        Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
        Circulation. 2012; 125: 1905-1919
        • Zhang Y.Z.
        • Da Silva J.R.
        • Reilly M.
        • Billheimer J.T.
        • Rothblat G.H.
        • et al.
        Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo.
        J. Clin. Invest. 2005; 115: 2870-2874
        • Phillips M.C.
        Molecular mechanisms of cellular cholesterol efflux.
        J. Biol. Chem. 2014; 289: 24020-24029
        • Tani M.
        • Horvath K.V.
        • Lamarche B.
        • Couture P.
        • Burnett J.R.
        • et al.
        High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency.
        Atherosclerosis. 2016; 253: 7-14
        • Zhang J.
        • Yu Y.
        • Nakamura K.
        • Koike T.
        • Waqar A.B.
        • et al.
        Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits.
        J. Atherosclerosis Thromb. 2012; 19: 213-226
        • Nijtad N.
        • Wiersma H.
        • Gautier T.
        • van der Giet M.
        • Maugeais C.
        • et al.
        Scavenger receptor BI-mediated selective uptake is required for the remodeling of high density lipoprotein by endothelial lipase.
        J. Biol. Chem. 2009; 284: 6093-6100