Horm Metab Res 2020; 52(04): 236-245
DOI: 10.1055/a-1116-2333
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Association of Apolipoprotein C3 Levels and Hepatic Steatosis: A Follow-Up Study

Patrick Heinz
1   Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
,
Bernhard Otto Boehm
2   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
3   Imperial College London, London, United Kingdom
,
Julian Schmidberger
1   Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
,
Wolfgang Kratzer
1   Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany
,
for the EMIL-Study Group › Author Affiliations
Funding Information Grants were received from the Baden-Württemberg State Health Office, the Stuttgart District Government, and the Ravensburg Regional Health Office. Further financial support was provided by the town council of Leutkirch, Germany. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG; GrK1041), Baden-Wuerttemberg, Germany and B Boehm’s Ong Tiong Tat Chair Professorship of Diabetes Research. This study was initiated by the government of the Federal State of Baden-Württemberg, Germany.
Further Information

Publication History

received 14 November 2019

accepted 30 January 2020

Publication Date:
28 February 2020 (online)

Abstract

Apolipoprotein C3 is a lipid-binding protein with a pivotal role in triglyceride metabolism and inflammation. This 11-year follow-up study aimed to evaluate apolipoprotein C3 levels and other parameters as markers of hepatic steatosis, in a random, population-based cohort in southern Germany. In 2013, we selected and re-examined 406 study participants (193 women, 213 men; average age 58.1±11.3 years) from the original “Echinococcus multilocularis and other internal diseases in Leutkirch I“ (EMIL I) cohort studied in 2002. All participants received upper abdominal sonography to grade potential hepatic steatosis, and blood tests to determine apolipoprotein C3 levels and other laboratory parameters. Body mass index, waist-to-hip ratio, and anthropometric measures were documented. The follow-up study conducted in 2013 included a partial correlation analysis. We found an association between hepatic steatosis and elevated apolipoprotein C3 levels (p<0.0001). Study participants with a novel diagnosis of hepatic steatosis had the highest apolipoprotein C3 serum levels (p=0.0002). Hepatic steatosis was associated with low levels of high density lipoprotein cholesterol (p=0.0374), high levels of total cholesterol (p=0.0117), increased homeostasis model assessment of insulin resistance (p=0.0002), elevated alanine transaminase (p<0.0001), elevated aspartate transaminase (p=0.0003), and elevated C-reactive protein (p=0.0446). Apolipoprotein C3 serum levels were associated with the presence, disease grade, and new development of hepatic steatosis likewise to biomarkers of the metabolic syndrome.

Supplementary Material

 
  • References

  • 1 Bellentani S, Bedogni G, Miglioli L. et al. The epidemiology of fatty liver. Eur J Gastroenterol Hepatol 2004; 16: 1087-1093
  • 2 Fan R, Wang J, Du J. Association between body mass index and fatty liver risk: A dose-response analysis. Sci Rep 2018; 8: 15273
  • 3 Bedogni G, Miglioli L, Masutti F. et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study. Hepatology 2005; 42: 44-52
  • 4 Stepanova M, Rafiq N, Makhlouf H. et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2013; 58: 3017-3023
  • 5 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231
  • 6 Qayyum A, Chen DM, Breiman RS. et al. Evaluation of diffuse use liver steatosis by ultrasound, computed tomography, and magnetic resonance imaging: Which modality is best?. Clin Imaging 2009; 33: 110-115
  • 7 Palmieri VO, Grattagliano I, Portincasa P. et al. Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr 2006; 136: 3022-3026
  • 8 Ryan MC, Wilson AM, Slavin J. et al. Associations between liver histology and severity of the metabolic syndrome in subjects with nonalcoholic fatty liver disease. Diabetes Care 2005; 28: 1222-1224
  • 9 Rector RS, Thyfault JP, Wei Y. et al. Non-alcoholic fatty liver disease and the metabolic syndrome: An update. World J Gastroenterol 2008; 14: 185-192
  • 10 Marchesini G, Bugianesi E, Forlani G. et al. Nonalcoholic Fatty Liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37: 917-923
  • 11 Goto T, Onuma T, Takebe K. et al. The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord 1995; 19: 841-845
  • 12 Nigam P, Bhatt SP, Misra A. et al. Non-Alcoholic fatty liver disease is closely associated with sub-clinical inflammation: A case-control study on Asian Indians in North India. PLoS One 2013; 8: e49286
  • 13 Kogiso T, Moriyoshi Y, Nagahara H. Clinical significance of fatty liver associated with metabolic syndrome. Hepatol Res 2007; 37: 711-721
  • 14 Park SH, Kim BI, Yun JW. et al. Insulin resistance and C-reactive protein as independent risk factors for non- alcoholic fatty liver disease in non-obese Asian men. J Gastroenterol Hepatol 2004; 19: 694-698
  • 15 Onat A, Hergenç G, Sansoy V. et al. Apolipoprotein C-III, a strong discriminant of coronary risk in men and a determinant of the metabolic syndrome in both genders. Atherosclerosis 2003; 168: 81-89
  • 16 Kawakami A, Aikawa M, Libby P. et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation 2006; 113: 691-700
  • 17 Libby P. Fat fuels the flame: Triglyceride-rich lipoproteins and arterial inflammation. Circ Res 2007; 100: 299-301
  • 18 Pollin TI, Damcott CM, Shen H. et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008; 322: 1702-1705
  • 19 Sacks FM, Alaupovic P, Moye LA. et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 2000; 102: 1886-1892
  • 20 Petersen KF, Dufour S, Hariri A. et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362: 1082-1089
  • 21 Niu TH, Jiang M, Xin YN. et al. Lack of association between apolipoprotein C3 gene polymorphisms and risk of nonalcoholic fatty liver disease in a Chinese Han population. World J Gastroenterol 2014; 20: 3655-3662
  • 22 Li MR, Zhang SH, Chao K. et al. Apolipoprotein C3 (-455T>C) polymorphism confers susceptibility to nonalcoholic fatty liver disease in the Southern Han Chinese population. World J Gastroenterol 2014; 20: 14010-14017
  • 23 Puppala J, Bhrugumalla S, Kumar A. et al. Apolipoprotein C3 gene polymorphisms in Southern Indian patients with nonalcoholic fatty liver disease. Indian J Gastroenterol 2014; 33: 524-529
  • 24 Verrijken A, Beckers S, Francque S. et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring) 2013; 21: 2138-2145
  • 25 Kozlitina J, Boerwinkle E, Cohen JC. et al. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 2011; 53: 467-474
  • 26 Hyysalo J, Stojkovic I, Kotronen A. et al. Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2012; 27: 951-956
  • 27 Valenti L, Nobili V, Al-Serri A. et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol 2011; 55: 1409-1414
  • 28 Sentinelli F, Romeo S, Maglio C. et al. Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. Lipids Health Dis 2011; 10: 93
  • 29 Haenle MM, Brockmann SO, Kron M. et al. Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 2006; 6: 233
  • 30 WHO: Physical status the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep 1995; 854: 427-437
  • 31 Protter AA, Levy-Wilson B, Miller J. et al. Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes. DNA 1984; 3: 449-456
  • 32 Nestel PJ, Fidge NH. Apoprotein C metabolism in man. Adv Lipid Res 1982; 19: 55-83
  • 33 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487-1495
  • 34 Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. BMJ 1986; 292: 13-15
  • 35 Hamaguchi M, Kojima T, Itoh Y. et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007; 102: 2708-2715
  • 36 Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis 2007; 11: 37-54
  • 37 Caballeria L, Pera G, Auladell MA. et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol 2010; 22: 24-32
  • 38 Browning JD, Szczepaniak LS, Dobbins R. et al. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004; 40: 1387-1395
  • 39 Hamaguchi M, Kojima T, Takeda N. et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143: 722-728
  • 40 Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference. Hepatology 2003; 37: 1202-1219
  • 41 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497
  • 42 Gaudet D, Brisson D, Tremblay K. et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med 2014; 371: 2200-2206
  • 43 Surendran RP, Visser ME, Heemelaar S. et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med 2012; 272: 185-196
  • 44 Chait A, Brunzell JD. Chylomicronemia syndrome. Adv Intern Med 1992; 37: 249
  • 45 LaRosa JC, Levy RI, Herbert P. et al. A specific apoprotein activator for lipoprotein lipase. Biochem Biophys Res Commun 1970; 41: 57-62
  • 46 Brown WV, Baginsky ML. Inhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein. Biochem Biophys Res Commun 1972; 46: 375-382
  • 47 Graham MJ, Lee RG, Bell TA. et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013; 112: 1479-1490
  • 48 Lee RG, Graham MJ, Fu W. et al. Antisense suppression of serum apoC-III improves hypertriglyceridemia and insulin sensitivity in multiple species. Diabetes 2013; 62 (Suppl 1A) LB14-LB14
  • 49 Alexander V, Gaudet D, Cheng W. et al. An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, very-low-density lipoprotein cholesterol and particle number, and increases high-density lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate. J Am Coll Cardiol 2014; 12 (Suppl) 63
  • 50 Gaudet D, Alexander VJ, Baker BF. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015; 373: 438-447
  • 51 Florentin M, Kostapanos MS, Anagnostis P. et al. Recent developments in pharmacotherapy for hypertriglyceridemia: What’s the current state oft he art?. Expert Opin Pharmacother 2020; 21: 17-120
  • 52 Stalenhoef AF, Demacker PN, Lutterman JA. et al. Apolipoprotein C in type 2 (non-insulin-dependent) diabetic patients with hypertriglyceridaemia. Diabetologia 1982; 22: 489-491
  • 53 McGarry JD, Dobbins R. Fatty acids, lipotoxicity and insulin secretion. Diabetologia 1999; 42: 128-138
  • 54 Waterworth DM, Talmud PJ, Luan J. et al. Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men. Biochimica et Biophysica Acta 2003; 1637: 200-206
  • 55 Juntti-Berggren L, Refai E, Appelskog I. et al. Apolipoprotein CIII promotes Ca2+-dependent beta cell death in type 1 diabetes. Proc Natl Acad Sci USA 2004; 101: 10090-10094
  • 56 Duseja A, Aggarwal R. APOC3 and PNPLA3 in non-alcoholic fatty liver disease: Need to clear the air. J Gastroenterol Hepatol 2012; 27: 848-851
  • 57 Kanth VV, Sasikala M, Rao PN. et al. Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects: A pilot study. World J Hepatol 2014; 27: 435-442
  • 58 Koehler EM, Schouten JN, Hansen BE. et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: Results from the Rotterdam study. J Hepatol 2012; 57: 1305-1311
  • 59 Lonardo A, Bellini M, Tartoni P. et al. The bright liver syndrome. Prevalence and determinants of a “bright” liver echopattern. Ital J Gastroenterol Hepatol 1997; 29: 351-356
  • 60 Bellentani S, Tiribelli C, Saccoccio G. et al. Prevalence of chronic liver disease in the general population of northern Italy: The Dionysos Study. Hepatology 1994; 20: 1442-1449
  • 61 Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z. et al. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int 2006; 26: 856-863
  • 62 Zhou YJ, Li YY, Nie YQ. et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol 2007; 13: 6419-6424
  • 63 Bedogni G, Miglioli L, Masutti F. et al. Incidence and natural course of fatty liver in the general population: The Dionysos study. Hepatology 2007; 46: 1387-1391