Skip to main content

Advertisement

SpringerLink
Log in

Association of Apolipoprotein E Polymorphisms in Patients with Non-Alcoholic Steatohepatitis

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of alcohol abuse worldwide. Non-alcoholic steatohepatitis (NASH) is the most progressive form of NAFLD. The aim of this study was to investigate the role of apolipoprotein E (APOE) polymorphisms in the development of NASH. We analysed 57 NASH patients and 245 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a case–control study. The diagnosis of the patients was based on liver biopsy. The serum levels of glucose, lipids, vitamin B12, folic acid, homocysteine, insulin, total biluribin, total protein, albumin, ferritin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined in all of the subjects. Body mass index (BMI), waist circumference (WC), AST, ALT, fasting blood sugar (FBS), total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, insulin and ferritin levels were significantly higher in the 57 patients with NASH compared with the 245 healthy controls. The APOE ε3 allele was overrepresented in the whole group of NASH patients (ε3=97.37% in NASH versus 82.45% in controls). The APOE polymorphism was statistically significantly associated with NASH (χ2=15.741; p=0.008). The APOE3/3 genotype (odds ratio [OR]=7.941; p=0.000) was strongly associated with increased risk for NASH in all NASH patients. Consequently, the APOE3/3 genotype may play a role in the aetiopathogenesis of NASH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438

    PubMed  CAS  Google Scholar 

  2. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231. doi:10.1056/NEJMra011775

    Article  PubMed  CAS  Google Scholar 

  3. Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G (2000) Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 45:1929–1934. doi:10.1023/A:1005661516165

    Article  PubMed  CAS  Google Scholar 

  4. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N (1999) Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107:450–455. doi:10.1016/S0002-9343(99)00271-5

    Article  PubMed  CAS  Google Scholar 

  5. Mehta K, Van Thiel DH, Shah N, Mobarhan S (2002) Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev 60:289–293. doi:10.1301/002966402320387224

    Article  PubMed  Google Scholar 

  6. Grove J, Brown AS, Daly AK, Bassendine MF, James OF, Day CP (1998) The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics 8:335–342. doi:10.1097/00008571-199808000-00007

    Article  PubMed  CAS  Google Scholar 

  7. Ohnishi T, Ogawa Y, Saibara T, Nishioka A, Kariya S, Fukumoto M, Onishi S, Yoshida S (2005) CYP17 polymorphism and tamoxifen-induced hepatic steatosis. Hepatol Res 33:178–180. doi:10.1016/j.hepres.2005.09.030

    Article  PubMed  CAS  Google Scholar 

  8. Nolan JP (1989) Intestinal endotoxins as mediators of hepatic injury—an idea whose time has come again. Hepatology 10:887–891. doi:10.1002/hep.1840100523

    Article  PubMed  CAS  Google Scholar 

  9. Tiegs G (1994) Immunotoxicology of host-response-mediated experimental liver injury. J Hepatol 21:890–903. doi:10.1016/S0168-8278(94)80256-4

    Article  PubMed  CAS  Google Scholar 

  10. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW (1998) Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114:311–318. doi:10.1016/S0016-5085(98)70482-2

    Article  PubMed  CAS  Google Scholar 

  11. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG (2001) The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48:206–211. doi:10.1136/gut.48.2.206

    Article  PubMed  CAS  Google Scholar 

  12. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM (2003) Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343–350. doi:10.1053/jhep.2003.50048

    Article  PubMed  CAS  Google Scholar 

  13. Utermann G, Hees M, Steinmetz A (1977) Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature 269:604–607. doi:10.1038/269604a0

    Article  PubMed  CAS  Google Scholar 

  14. Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR, Blum C (1982) Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res 23:911–914

    PubMed  CAS  Google Scholar 

  15. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5):1977–1981. doi:10.1073/pnas.90.5.1977

    Article  PubMed  CAS  Google Scholar 

  16. Parmenter BA, Denney DR, Lynch SG, Middleton LS, Harlan LM (2007) Cognitive impairment in patients with multiple sclerosis: association with the APOE gene and promoter polymorphisms. Mult Scler 13(1):25–32. doi:10.1177/1352458506070682

    Article  PubMed  CAS  Google Scholar 

  17. Pezzini A, Grassi M, Del Zotto E, Bazzoli E, Archetti S, Assanelli D, Akkawi NM, Albertini A, Padovani A (2004) Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults. Stroke 35(2):438–442. doi:10.1161/01.STR.0000112973.00867.98

    Article  PubMed  CAS  Google Scholar 

  18. Li YJ, Pericak-Vance MA, Haines JL, Siddique N, McKenna-Yasek D, Hung WY, Sapp P, Allen CI, Chen W, Hosler B, Saunders AM, Dellefave LM, Brown RH, Siddique T (2004) Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis. Neurogenetics 5(4):209–213. doi:10.1007/s10048-004-0193-0

    Article  PubMed  CAS  Google Scholar 

  19. Rainero I, Grimaldi LME, Salani G, Valfrè W, Savi L, Rivoiro C, Gentile S, Pinessi L (2002) Apolipoprotein E gene polymorphisms in patients with migraine. Neurosci Lett 317:111–113. doi:10.1016/S0304-3940(01)02432-6

    Article  PubMed  CAS  Google Scholar 

  20. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. doi:10.1093/nar/16.3.1215

    Article  PubMed  CAS  Google Scholar 

  21. Wenham PR, Price WH, Blundel G (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet 337:1158–1159. doi:10.1016/0140-6736(91)92823-K

    Article  PubMed  CAS  Google Scholar 

  22. Sazci A, Ergul E, Kaya G, Kara I (2005) Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey. Cell Biochem Funct 23:51–54. doi:10.1002/cbf.1132

    Article  PubMed  CAS  Google Scholar 

  23. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474. doi:10.1111/j.1572-0241.1999.01377.x

    Article  PubMed  CAS  Google Scholar 

  24. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321. doi:10.1002/hep.20701

    Article  PubMed  Google Scholar 

  25. Demirag MD, Onen HI, Karaoguz MY, Dogan I, Karakan T, Ekmekci A, Guz G (2007) Apolipoprotein E gene polymorphism in nonalcoholic fatty liver disease. Dig Dis Sci 52(12):3399–3403. doi:10.1007/s10620-007-9740-5

    Article  PubMed  CAS  Google Scholar 

  26. Price DA, Bassendine MF, Norris SM, Golding C, Toms GL, Schmid ML, Morris CM, Burt AD, Donaldson PT (2006) Apolipoprotein epsilon3 allele is associated with persistent hepatitis C virus infection. Gut 55:715–718. doi:10.1136/gut.2005.079905

    Article  PubMed  CAS  Google Scholar 

  27. Yang MH, Son HJ, Sung JD, Choi YH, Koh KC, Yoo BC, Paik SW (2005) The relationship between apolipoprotein E polymorphism, lipoprotein (a) and fatty liver disease. Hepatogastroenterology 52:1832–1835

    PubMed  CAS  Google Scholar 

  28. Yoshimatsu M, Terasaki Y, Sakashita N, Kiyota E, Sato H, van der Laan LJ, Takeya M (2004) Induction of macrophage scavenger receptor MARCO in nonalcoholic steatohepatitis indicates possible involvement of endotoxin in its pathogenic process. Int J Exp Pathol 85:335–343. doi:10.1111/j.0959-9673.2004.00401.x3

    Article  PubMed  Google Scholar 

  29. Miller JL (2003) Insulin resistance syndrome. Description, pathogenesis, and management. Postgrad Med 113:27–34

    Google Scholar 

  30. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923. doi:10.1053/jhep.2003.50161

    Article  PubMed  Google Scholar 

  31. Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF (2002) Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 34:616–621. doi:10.1055/s-2002-38256

    Article  PubMed  CAS  Google Scholar 

  32. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946. doi:10.1038/90984

    Article  PubMed  CAS  Google Scholar 

  33. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336. doi:10.1038/nature01137

    Article  PubMed  CAS  Google Scholar 

  34. Huang Y, Liu XQ, Rall SC Jr, Taylor JM, von Eckardstein A, Assmann G, Mahley RW (1998) Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem 273:26388–26393. doi:10.1074/jbc.273.41.26388

    Article  PubMed  CAS  Google Scholar 

  35. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845. doi:10.1016/S0016-5085(98)70599-2

    Article  PubMed  CAS  Google Scholar 

  36. Goossens V, Grooten J, De Vos K, Fiers W (1995) Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA 92:8115–8119. doi:10.1073/pnas.92.18.8115

    Article  PubMed  CAS  Google Scholar 

  37. Pessayre D, Mansouri A, Fromenty B (2002) Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. Am J Physiol Gastrointest Liver Physiol 282:G193–G199

    PubMed  CAS  Google Scholar 

  38. Shiri-Sverdlov R, Wouters K, van Gorp PJ, Gijbels MJ, Noel B, Buffat L, Staels B, Maeda N, van Bilsen M, Hofker MH (2006) Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J Hepatol 44:732–741. doi:10.1016/j.jhep.2005.10.033

    Article  PubMed  CAS  Google Scholar 

  39. Lessner SM, Prado HL, Waller EK, Galis ZS (2002) Atherosclerotic lesions grow through recruitment and proliferation of circulating monocytes in a murine model. Am J Pathol 160:2145–2155

    PubMed  CAS  Google Scholar 

  40. Grainger DJ, Reckless J, McKilligin E (2004) Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice. J Immunol 173:6366–6375

    PubMed  CAS  Google Scholar 

  41. Tous M, Ferré N, Camps J, Riu F, Joven J (2005) Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis. Mol Cell Biochem 268:53–58. doi:10.1007/s11010-005-2997-0

    Article  PubMed  CAS  Google Scholar 

  42. Mensenkamp AR, Van Luyn MJ, Havinga R, Teusink B, Waterman IJ, Mann CJ, Elzinga BM, Verkade HJ, Zammit VA, Havekes LM, Shoulders CC, Kuipers F (2004) The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice. J Hepatol 40:599–606. doi:10.1016/j.jhep.2003.12.011

    Article  PubMed  CAS  Google Scholar 

  43. Demant T, Bedford D, Packard CJ, Shepherd J (1991) Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipidemic subjects. J Clin Invest 88:1490–1501. doi:10.1172/JCI115459

    Article  PubMed  CAS  Google Scholar 

  44. Welty FK, Lichtenstein AH, Barrett PH, Jenner JL, Dolnikowski GG, Schaefer EJ (2000) Effects of ApoE genotype on ApoB-48 and ApoB-100 kinetics with stable isotopes in humans. Arterioscler Thromb Vasc Biol 20:807–1810

    Google Scholar 

  45. Riches FM, Watts GF, van Bockxmeer FM, Hua J, Song S, Humphries SE, Talmud PJ (1998) Apolipoprotein B signal peptide and apolipoprotein E genotypes as determinants of the hepatic secretion of VLDL apoB in obese men. J Lipid Res 39:1752–1758

    PubMed  CAS  Google Scholar 

  46. Mensenkamp AR, Havekes LM, Romijn JA, Kuipers F (2001) Hepatic steatosis and very low density lipoprotein secretion: the involvement of apolipoprotein E. J Hepatol 35:816–822. doi:10.1016/S0168-8278(01)00249-5

    Article  PubMed  CAS  Google Scholar 

  47. Sazci A, Akpinar G, Aygun C, Ergul E, Senturk O, Hulagu S (2006) Apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis (NASH). J Hepatol 44:S263–S263 715 Suppl. 2

    Google Scholar 

  48. Kasap M, Sazci A, Akpinar G, Ergul E (2008) Apolipoprotein E phylogeny and evolution. Cell Biochem Funct 26(1):43–50. doi:10.1002/cbf.1396

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Biology and Genetics, Faculty of Medicine, University of Kocaeli, Umuttepe, Kocaeli, 41380, Turkey

    Ali Sazci, Gurler Akpinar & Emel Ergul

  2. Department of Gastroenterology, Faculty of Medicine, University of Kocaeli, Umuttepe, Kocaeli, 41380, Turkey

    Cem Aygun, Omer Senturk & Sadettin Hulagu

Authors
  1. Ali Sazci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gurler Akpinar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cem Aygun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emel Ergul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omer Senturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sadettin Hulagu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Sazci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sazci, A., Akpinar, G., Aygun, C. et al. Association of Apolipoprotein E Polymorphisms in Patients with Non-Alcoholic Steatohepatitis. Dig Dis Sci 53, 3218–3224 (2008). https://doi.org/10.1007/s10620-008-0271-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-008-0271-5

Keywords

Search

Navigation