Genetische Modulatoren der nichtalkoholischen Fettlebererkrankung

Zusammenfassung

Die nicht-alkoholische Fettlebererkrankung (NAFLD) ist heute eine der häufigsten chronischen Lebererkrankungen und wird aufgrund steigender Prävalenz in den nächsten Jahren zur häufigsten Ursache für Lebertransplantationen. Neben einem ungesunden Lebensstil spielen auch genetische sowie epigenetische Faktoren eine Rolle bei der NAFLD-Pathogenese und dem Schweregrad der Erkrankung. Dabei werden alle Verlaufsstadien der NAFLD, von der Insulinresistenz und hepatischen Lipidakkumulation über die nicht-alkoholische Steatohepatitis mit Schädigung der Leberzellen und Fibrose bis hin zum mögli-chen Endstadium, der Leberzirrhose und dem hepatozellulären Karzinom, von genetischen Faktoren beeinflusst. Eine Analyse dieser interindividuellen genetischen Unterschiede ist wichtig für 1) eine sichere und frühzeitige Diagnose der NAFLD, 2) zur Identifizierung von Patienten mit dem Risiko zur Progression und 3), um neue Therapiemöglichkeiten zu entwickeln. Dieser Artikel diskutiert die derzeit bekannten krankheitsrelevanten Genvarianten und wie diese die Entstehung und Progression der NAFLD beeinflussen.

Summary

To date, non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases and is thought to become the most frequent cause for liver transplantation in the near future. Besides an unhealthy life style, genetic and epigenetic factors are playing an important role in determining NAFLD pathogenesis and severity. Genetic factors have an influence on all stages of NAFLD, ranging from insulin resistance and hepatic lipid accumulation, non-alcoholic steatohepatitis and fibrosis to end-stage liver disease and hepatocellular carcinoma. Analysis of these between-subject genetic differences is important for a more secure and early diagnosis of NAFLD, to identify patients at risk of NAFLD progression and to develop novel therapy opportunities. This review discusses the currently known disease-relevant genetic variants and how they exert their influence on development and progression of NAFLD.

Schlüsselwörter

NAFLD - Genetik - NASH - Polymorphismus

Keywords

NAFLD - genetics - NASH - polymorphism

• Literatur

• 1 Bellentani S, Scaglioni F, Marino M. et al. Epidemiology of Non-Alcoholic Fatty Liver Disease. Dig Dis 2010; 28: 155-161.
• 2 Bedogni G, Miglioli L, Masutti F. Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study. Hepatology 2005; 42: 44-52.
• 3 Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10: 645-655.
• 4 Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21: 11088
• 5 Speliotes EK, Yerges-Armstrong LM, Wu J. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. McCarthy MI. (ed) PLoS Genet 2011; 7-e1001324.
• 6 Loomba R, Schork N, Chen C-H et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015; 149: 1784-1793.
• 7 Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics. Gut. BMJ Group; 65. 1895
• 8 Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-1465.
• 9 Noto H, Osame K, Sasazuki T, Noda M. Substantially increased risk of cancer in patients with diabetes mellitus: a systematic review and metaanalysis of epidemiologic evidence in Japan. J Diabetes Complications 2010; 24: 345-353.
• 10 Valenti L, Alisi A, Nobili V. Unraveling the genetics of fatty liver in obese children: Additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Hepatology 2012; 55: 661-663.
• 11 Vazquez-Chantada M, Gonzalez-Lahera A, Martinez-Arranz I. Et al. Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease. Hepatology 2013; 57: 505-514.
• 12 Gawrieh S, Marion MC, Komorowski R. Genetic variation in the peroxisome proliferator activated receptor-gamma gene is associated with histologically advanced NAFLD. Dig Dis Sci 2012; 57: 952-957.
• 13 Dongiovanni P, Valenti L, Rametta R. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 2010; 59: 267-273.
• 14 He S, McPhaul C, Li JZ. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285: 6706-6715.
• 15 Smagris E, BasuRay S, Li J. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61: 108-118.
• 16 Auinger A, Valenti L, Pfeuffer M. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res 2010; 42: 854-859.
• 17 Teslovich TM, Musunuru K, Smith AV. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466: 707-713.
• 18 Kitamoto A, Kitamoto T, Nakamura T. Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. Endocr J 2014; 61: 683-689.
• 19 Liu Y-L, Reeves HL, Burt AD. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014; 5: 4309
• 20 Kozlitina J, Smagris E, Stender S. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46: 352-356.
• 21 Li JZ, Huang Y, Karaman R. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122: 4130-4144.
• 22 Gorden A, Yang R, Yerges-Armstrong LM. et al. Genetic Variation at NCAN Locus Is Associated with Inflammation and Fibrosis in Non-Alcoholic Fatty Liver Disease in Morbid Obesity. Hum Hered 2013; 75: 34-43.
• 23 Petta S, Miele L, Bugianesi E. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. Villa E (ed). PLoS One 2014; 9: e87523
• 24 Namikawa C, Shu-Ping Z, Vyselaar JR. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40: 781-786.
• 25 Al-Serri A, Anstee QM, Valenti L. et a.l The SOD2 C47T polymorphism influences NAFLD fibrosis severity: Evidence from case-control and intrafamilial allele association studies. J Hepatol 2012; 56: 448-454.
• 26 Miele L, Beale G, Patman G. et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 2008; 135: 282-291.e1.
• 27 Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H. et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009; 29: 1078-1085.
• 28 Zain SM, Mohamed Z, Mahadeva S. et al. Susceptibility and Gene Interaction Study of the Angiotensin II Type 1 Receptor (AGTR1) Gene Polymorphisms with Non-Alcoholic Fatty Liver Disease in a Multi-Ethnic Population. Uddin M (ed). PLoS One 2013; 8: e58538
• 29 Moreno M, Gonzalo T, Kok RJ. et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010; 51: 942-952.
• 30 Yokohama S, Yoneda M, Haneda M. et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004; 40: 1222-1225.
• 31 Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10: 686-690.
• 32 Takeuchi Y, Ikeda F, Moritou Y. et al. The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis. J Gastroenterol 2013; 48: 405-412.
• 33 Burza MA, Pirazzi C, Maglio C. et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012; 44: 1037-1041.
• 34 da Silva RP, Kelly KB, Al Rajabi A. et al. Novel insights on interactions between folate and lipid metabolism. Biofactors 2014; 40: 277-283.
• 35 Guarente L, Imai S, Armstrong CM. et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000; 403: 795-800.
• 36 Zeybel M, Hardy T, Wong YK. et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med 2012; 18: 1369-1377.
• 37 Sookoian S, Rosselli MS, Gemma C. et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010; 52: 1992-2000.
• 38 Pirola CJ, Fernández Gianotti T, Castaño GO. et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015; 64: 800-812.
• 39 Miyaaki H, Ichikawa T, Kamo Y. et al. Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease. Liver Int 2014; 34: e302-307.
• 40 Dattaroy D, Pourhoseini S, Das S. et al. Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol – Gastrointest Liver Physiol 2015; 308: G298-312.