Serum lipoprotein(a) levels and insulin resistance have opposite effects on fatty liver disease


      • The association between Lp(a) and fatty liver disease (FLD) remains controversial.
      • Serum Lp(a) levels were inversely associated with the presence of FLD.
      • Subjects with low Lp(a) and high insulin resistance (IR) showed an increased risk of FLD.


      Background and aims

      High lipoprotein(a) [Lp(a)] levels are associated with increased risk of cardiovascular disease. However, the association between Lp(a) and fatty liver disease (FLD) remains controversial. Therefore, we analyzed the relationship between FLD and serum Lp(a) levels in Korean adults.


      A total of 22,534 participants who underwent a routine health screening program at Kangbuk Samsung Hospital in 2010 and 2014 were enrolled. Anthropometric and biochemical parameters, including Lp(a), were measured. The presence of FLD was assessed using abdominal ultrasonography. Odds ratios (ORs) for the presence of FLD were analyzed in quartile groups of serum Lp(a) levels using logistic regression. We divided the participants into four groups according to the median values of Lp(a) and homeostasis model assessment for insulin resistance (HOMA-IR).


      Among the total study population, 3030 (13.4%) participants had fatty liver disease. The mean Lp(a) level was lower in subjects with FLD than in those without (70.0 vs 73.8 nmol/L, p < 0.001). The OR for FLD was the lowest in the fourth Lp(a) quartile group, using the first quartile group as the reference group after adjusting for confounding factors [0.815; 95% confidence interval (CI) 0.725–0.916]. When the OR for FLD was analyzed in four groups divided by the median values of Lp(a) and HOMA-IR, the low Lp(a)-high HOMA-IR group had the greatest OR for FLD, using the high Lp(a)-low HOMA-IR group as the reference (1.903; 95% CI 1.679–2.158).


      Serum Lp(a) levels were inversely associated with the presence of FLD. Subjects with low Lp(a) and high insulin resistance (IR) showed higher risk of FLD than those with high Lp(a) and low IR, suggesting the opposite associations of Lp(a) and IR with FLD.

      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


        • Kronenberg F.
        Human genetics and the causal role of lipoprotein(a) for various diseases.
        Cardiovasc. Drugs Ther. 2016; 30: 87-100
        • Boerwinkle E.
        • Leffert C.C.
        • Lin J.
        • Lackner C.
        • Chiesa G.
        • Hobbs H.H.
        Apolipoprotein (a) gene accounts for greater than 90% of the variation in plasma lipoprotein (a) concentrations.
        J. Clin. Invest. 1992; 90: 52-60
        • Brown W.V.
        • Moriarty P.M.
        • Remaley A.T.
        • Tsimikas S.
        JCL Roundtable: should we treat elevations in Lp(a)?.
        J. Clin. Lipidol. 2016; 10: 215-224
        • Nordestgaard B.G.
        • Chapman M.J.
        • Ray K.
        • Borén J.
        • Andreotti F.
        • Watts G.F.
        • et al.
        European Atherosclerosis Society Consensus Panel, Lipoprotein(a) as a cardiovascular risk factor: current status.
        Eur. Heart J. 2010; 31: 2844-2853
        • Reyes-Soffer G.
        • Ginsberg H.N.
        • Ramakrishnan R.
        The metabolism of lipoprotein (a): an ever-evolving story.
        J. Lipid Res. 2017; 58: 1756-1764
        • Mora S.
        • Kamstrup P.R.
        • Rifai N.
        • Nordestgaard B.G.
        • Buring J.E.
        • Ridker P.M.
        Lipoprotein (a) and risk of type 2 diabetes.
        Clin. Chem. 2010; 56: 1252-1260
        • Sung K.C.
        • Wild S.H.
        • Byrne C.D.
        Lipoprotein (a), metabolic syndrome and coronary calcium score in a large occupational cohort.
        Nutr. Metabol. Cardiovasc. Dis. 2013; 23: 1239-1246
        • Rinella M.
        • Charlton M.
        The globalization of nonalcoholic fatty liver disease: prevalence and impact on world health.
        Hepatology. 2016; 64: 19-22
        • Rhee E.J.
        Nonalcoholic fatty liver disease and diabetes: an epidemiological perspective.
        Endocrinol. Metab. (Seoul). 2019; 34: 226-233
        • Gutierrez-Buey G.
        • Núñez-Córdoba J.M.
        • Llavero-Valero M.
        • Gargallo J.
        • Salvador J.
        • Escalada J.
        Is HOMA-IR a potential screening test for non-alcoholic fatty liver disease in adults with type 2 diabetes?.
        Eur. J. Intern. Med. 2017; 41: 74-78
        • Marchesini G.
        • Brizi M.
        • Morselli-Labate A.M.
        • Bianchi G.
        • Bugianesi E.
        • McCullough A.J.
        • et al.
        Association of nonalcoholic fatty liver disease with insulin resistance.
        Am. J. Med. 1999; 107: 450-455
        • Utzschneider K.M.
        • Kahn S.E.
        Review: the role of insulin resistance in nonalcoholic fatty liver disease.
        J. Clin. Endocrinol. Metab. 2006; 91: 4753-4761
        • Adams L.A.
        • Anstee Q.M.
        • Tilg H.
        • Targher G.
        Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
        Gut. 2017; 66: 1138-1153
        • Mathiesen U.L.
        • Franzén L.E.
        • Aselius H.
        • Resjö M.
        • Jacobsson L.
        • Foberg U.
        • et al.
        Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.
        Dig. Liver Dis. 2002; 34: 516-522
        • Kim C.W.
        • Yun K.E.
        • Jung H.S.
        • Chang Y.
        • Choi E.S.
        • Kwon M.J.
        • et al.
        Sleep duration and quality in relation to non-alcoholic fatty liver disease in middle-aged workers and their spouses.
        J. Hepatol. 2013; 59: 351-357
        • Nam J.S.
        • Jo S.
        • Kang S.
        • Ahn C.W.
        • Kim K.R.
        • Park J.S.
        Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults.
        Clin. Chim. Acta. 2016; 461: 14-18
        • Choe Y.G.
        • Jin W.
        • Cho Y.K.
        • Chung W.G.
        • Kim H.J.
        • Jeon W.K.
        • et al.
        Apolipoprotein B/AI ratio is independently associated with non‐alcoholic fatty liver disease in nondiabetic subjects.
        J. Gastroenterol. Hepatol. 2013; 28: 678-683
        • Yang M.H.
        • Son H.J.
        • Sung J.D.
        • Choi Y.H.
        • Koh K.C.
        • Yoo B.C.
        • et al.
        The relationship between apolipoprotein E polymorphism, lipoprotein (a) and fatty liver disease.
        Hepato-Gastroenterology. 2005; 52: 1832-1835
        • Uchil D.
        • Pipalia D.
        • Chawla M.
        • PatelR R.
        • Maniar S.
        • Narayani
        • et al.
        Non-alcoholic fatty liver disease (NAFLD)—the hepatic component of metabolic syndrome.
        J. Assoc. Phys. India. 2009; 57: 201
        • Kato K.
        • Takeshita Y.
        • Misu H.
        • Zen Y.
        • Kaneko S.
        • Takamura T.
        Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in J apanese patients with non‐alcoholic fatty liver disease.
        J. Diabetes. Invest. 2015; 6: 158-163
        • Tamura S.
        • Shimomura I.
        Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease.
        J. Clin. Invest. 2005; 115: 1139-1142
        • Haffner S.M.
        • Karhapaa P.
        • Rainwater D.L.
        • Mykkanen L.
        • Jr Aldrete G.
        • Laakso M.
        Insulin sensitivity and Lp (a) concentrations in normoglycemic men.
        Diabetes Care. 1995; 18: 193-199
        • Neele D.M.
        • de Wit E.C.
        • Princen H.M.
        Insulin suppresses apolipoprotein (a) synthesis by primary cultures of cynomolgus monkey hepatocytes.
        Diabetologia. 1999; 42: 41-44
        • Vaverková H.
        • Karásek D.
        • Halenka M.
        • Cibíčková L.
        • Kubíčková V.
        Inverse association of lipoprotein (a) with markers of insulin resistance in dyslipidemic subjects.
        Physiol. Res. 2017; 66: S113
        • Guan W.
        • Cao J.
        • Steffen B.T.
        • Post W.S.
        • Stein J.H.
        • Tattersall M.C.
        • et al.
        Race is a key variable in assigning ipoprotein (a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis, Arterioscler.
        Thromb. Vasc. Biol. 2015; 35: 996-1001
        • Kozakova M.
        • Palombo C.
        • Eng M.P.
        • Dekker J.
        • Flyvbjerg A.
        • Mitrakou A.
        • et al.
        RISC Investigators, Fatty liver index, gamma‐glutamyltransferase, and early carotid plaques.
        Hepatology. 2012; 55: 1406-1415
        • Lee Y.H.
        • Jung K.S.
        • Kim S.U.
        • Yoon H.J.
        • Yun Y.J.
        • Lee B.W.
        • et al.
        Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: nationwide surveys (KNHANES 2008–2011).
        J. Hepatol. 2015; 63: 486-493