Non-alcoholic fatty liver disease--a chronic disease of the 21^st century

Abstract

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of metabolic states ranging from simple steatosis to inflammation with associated fibrosis to cirrhosis. Though accumulation of hepatic fat is not associated with a significant increase in mortality rates, hepatic inflammation is, as this augments the risk of terminal liver disease, i.e., cirrhosis, hepatic decompensation (liver failure) and/or hepatocellular carcinoma. Disease progression is usually slow, over a decade or more and, for the most part, remains asymptomatic. Recent estimates suggest that the global prevalence of NAFLD is high, about one in four. In most cases, NAFLD overlaps with overweight, obesity, cardiovascular disease and the metabolic syndrome with numerous contributing parameters including a dysregulation of adipose tissue, insulin resistance, type 2 diabetes, changes in the gut microbiome, neuronal and hormonal dysregulation and metabolic stress. NAFLD is diagnosed incidentally, despite its high prevalence. Non-invasive imaging techniques have emerged, making it possible to determine degree of steatosis as well asfibrosis. Despite this, the benefit of routine diagnostics remains uncertain. A better understanding of the (molecular) pathogenesis of NAFLD is needed combined with long-term studies where benefits of treatment can be assessed to determine cost-benefit ratios. This review summarizes the current state of knowledge and possible areas of treatment.

Keywords

non-alcoholic fatty liver disease / pathogenesis / molecular mechanism / diagnostics / biomarker

References

[1] Younossi ZM, Koenig AB, Abdelatif D, Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes[J]. Hepatology, 2016, 64(1):73–84.

[2] Ekstedt M, Hagstrom H, Nasr P, Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up[J]. Hepatology, 2015, 61(5): 1547–1554.

[3] Stepanova M, Rafiq N, Makhlouf H, Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD)[J]. Dig Dis Sci, 2013, 58(10): 3017–3023.

[4] Portillo-Sanchez P, Bril F, Maximos M, High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels[J]. J Clin Endocrinol Metab, 2015, 100(6): 2231–2238.

[5] Page JM, Harrison SA. NASH and HCC[J]. Clin Liver Dis, 2009, 13(4): 631–647.

[6] Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection[J]. Hepatology, 2010, 51(5): 1820–1832.

[7] Davis GL, Dempster J, Meler JD, Hepatocellular carcinoma: management of an increasingly common problem[J]. Proc Bayl Univ Med Cent, 2008, 21: 266–280.

[8] Ravikumar R, Jassem W, Mergental H, Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial[J]. Am J Transplant, 2016, 16(6): 1779–1787.

[9] European Association for the Study of the Liver. Electronic address eee, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease[J]. J Hepatol, 2016, 64(6): 1388–1402

[10] Assy N, Kaita K, Mymin D, Fatty infiltration of liver in hyperlipidemic patients[J]. Dig Dis Sci, 2000, 45(10): 1929–1934

[11] Ratziu V, Charlotte F, Heurtier A, Sampling variability of liver biopsy in nonalcoholic fatty liver disease[J]. Gastroenterology, 2005, 128(7): 1898–1906.

[12] Janiec DJ, Jacobson ER, Freeth A, Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies[J]. Obes Surg, 2005, 15(4): 497–501.

[13] Jung ES, Lee K, Yu E, Interobserver Agreement on Pathologic Features of Liver Biopsy Tissue in Patients with Nonalcoholic Fatty Liver Disease[J]. J Pathol Transl Med, 2016, 50(3): 190–196.

[14] Verlinden W, Bourgeois S, De Maeyer M, Validation of APRI and FIB-4 score in an Antwerp cohort of chronic hepatitis C patients[J]. Acta Gastroenterol Belg, 2015, 78: 373–380.

[15] Lee JH, Kim D, Kim HJ, Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease[J]. Dig Liver Dis, 2010, 42(7): 503–508.

[16] Chalasani N, Younossi Z, Lavine JE, The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association[J]. Hepatology, 2012, 55(6): 2005–2023.

[17] Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice[J]. J Hepatol, 2016, 65(5): 1006–1016.

[18] Kwok R, Tse YK, Wong GL, Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease–the role of transient elastography and plasma cytokeratin-18 fragments[J]. Aliment Pharmacol Ther, 2014, 39(3): 254–269.

[19] Sandrin L, Fourquet B, Hasquenoph JM, Transient elastography: a new noninvasive method for assessment of hepatic fibrosis[J]. Ultrasound Med Biol, 2003, 29(12): 1705–1713

[20] Sebastiani G, Tempesta D, Fattovich G, Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: Results of a multicenter, large-scale study[J]. J Hepatol, 2010, 53(4): 630–638.

[21] Lee SS, Park SH, Kim HJ, Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations[J]. J Hepatol, 2010, 52(4): 579–585.

[22] Al-Busafi SA, Ghali P, Wong P, The utility of Xenon-133 liver scan in the diagnosis and management of nonalcoholic fatty liver disease[J]. Can J Gastroenterol, 2012, 26(3): 155–159.

[23] Sebastiani G, Alshaalan R, Wong P, Prognostic value of non-invasive fibrosis and steatosis tools, hepatic venous pressure gradient (HVPG) and histology in nonalcoholic steatohepatitis[J]. PLoS One, 2015, 10(6): e0128774

[24] Angulo P, Bugianesi E, Bjornsson ES, Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease[J]. Gastroenterology, 2013;145:782–9 e4.

[25] Hannah WN Jr, Harrison SA. Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Hepatology, 2016;64(6):2234–2243.

[26] Bedossa P, Patel K.Biopsy and noninvasive methods to assess progression of nonalcoholic fatty liver disease[J]. Gastroenterology. 2016;150:1811–22 e4.

[27] Ibrahim SH, Hirsova P, Malhi H, Animal models of nonalcoholic steatohepatitis: eat, delete, and inflame[J]. Dig Dis Sci, 2016, 61(5): 1325–1336

[28] Sanches SC, Ramalho LN, Augusto MJ, . Nonalcoholic steatohepatitis: a search for factual animal models[J]. biomed research international. 2015;2015:574832.

[29] Collins FS. Reengineering translational science: the time is right[J]. Sci Transl Med, 2011, 3(90): 90cm17

[30] Sartipy P, Bjorquist P. Concise review: Human pluripotent stem cell-based models for cardiac and hepatic toxicity assessment[J]. Stem Cells, 2011, 29(5): 744–748.

[31] Singh M, Ferrara N. Modeling and predicting clinical efficacy for drugs targeting the tumor milieu[J]. Nat Biotechnol, 2012, 30(7): 648–657.

[32] Raven K. Rodent models of sepsis found shockingly lacking[J]. Nat Med, 2012, 18(7): 998.

[33] Mullane K, Williams M. Translational semantics and infrastructure: another search for the emperor’s new clothes[J]? Drug Discov Today, 2012, 17(9-10): 459–468.

[34] Thorogood A, Joly Y, Knoppers BM, An implementation framework for the feedback of individual research results and incidental findings in research[J]. BMC Med Ethics, 2014, 15(1): 88.

[35] Romeo S, Kozlitina J, Xing C, Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet, 2008, 40(12): 1461–1465.

[36] Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease[J]. Hepatology, 2011, 53(6): 1883–1894.

[37] Speliotes EK, Butler JL, Palmer CD, PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease[J]. Hepatology, 2010, 52(3): 904–912

[38] Rotman Y, Koh C, Zmuda JM, The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease[J]. Hepatology, 2010, 52(3): 894–903

[39] Valenti L, Alisi A, Galmozzi E, I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease[J]. Hepatology, 2010, 52(4): 1274–1280

[40] Valenti L, Al-Serri A, Daly AK, Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease[J]. Hepatology, 2010, 51(4): 1209–1217

[41] Kozlitina J, Smagris E, Stender S, Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet, 2014, 46(4): 352–356

[42] Smagris E, Gilyard S, BasuRay S, Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins[J]. J Biol Chem, 2016, 291(20): 10659–10676

[43] Petersen KF, Dufour S, Hariri A, Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease[J]. N Engl J Med, 2010, 362(12): 1082–1089

[44] Burger M, Zimmermann TJ, Kondoh Y, Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases[J]. J Lipid Res, 2012, 53(1): 43–50

[45] Wood KL, Miller MH, Dillon JF. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease[J]. BMJ Open Gastroenterol, 2015, 2(1): e000019

[46] Pirola CJ, Fernandez Gianotti T, Castano GO, Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis[J]. Gut, 2015, 64(5): 800–812

[47] Aagaard-Tillery KM, Grove K, Bishop J, Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome[J]. J Mol Endocrinol, 2008, 41(2): 91–102

[48] Jun HJ, Kim J, Hoang MH, Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network[J]. PLoS One, 2012, 7(9): e44345

[49] Eslam M, George J. Genetic and epigenetic mechanisms of NASH[J]. Hepatol Int, 2016, 10(3): 394–406

[50] Gallego-Durán R, Romero-Gomez M. Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field[J]. World J Hepatol, 2015, 7(24): 2497–2502.

[51] Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism, 2016, 65(8): 1038–1048.

[52] Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease[J]. J Biomed Res, 2013, 27(1): 1–13

[53] Bernelot Moens SJ, van Capelleveen JC, Stroes ES. Inhibition of ApoCIII: the next PCSK9[J]? Curr Opin Lipidol, 2014, 25(6): 418–422.

[54] McConathy WJ, Gesquiere JC, Bass H, Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C–III[J]. J Lipid Res, 1992, 33: 995–1003.

[55] Qin W, Sundaram M, Wang Y, Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen[J]. J Biol Chem, 2011, 286(31): 27769–27780.

[56] Holleboom AG, Karlsson H, Lin RS, Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man[J]. Cell Metab, 2011, 14(6): 811–818

[57] Ertunc ME, Sikkeland J, Fenaroli F, Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity[J]. J Lipid Res, 2015, 56(2): 423–434.

[58] Deretic V, Jiang S, Dupont N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation[J]. Trends Cell Biol, 2012, 22(8): 397–406.

[59] Mao Y, Yu F, Wang J, Autophagy: a new target for nonalcoholic fatty liver disease therapy[J]. Hepat Med, 2016, 8: 27–37.

[60] Kennedy OJ, Roderick P, Poole R, Coffee, caffeine and non-alcoholic fatty liver disease[J]? Therap Adv Gastroenterol, 2016, 9(3): 417–418.

[61] Marventano S, Salomone F, Godos J, Coffee and tea consumption in relation with non-alcoholic fatty liver and metabolic syndrome: A systematic review and meta-analysis of observational studies[J]. Clin Nutr, 2016, 35(6): 1269–1281.

[62] Sinha RA, Farah BL, Singh BK, Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice[J]. Hepatology, 2014, 59(4): 1366–1380.

[63] Ding WX. Drinking coffee burns hepatic fat by inducing lipophagy coupled with mitochondrial beta-oxidation[J]. Hepatology, 2014, 59(4): 1235–1238.

[64] Wong AT, Chan DC, Ooi EM, Omega-3 fatty acid ethyl ester supplementation decreases very-low-density lipoprotein triacylglycerol secretion in obese men[J]. Clin Sci, 2013, 125(1): 45–51.

[65] Chen Y, Xu C, Yan T, . omega-3 Fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease[J]. Nutrition, 2015;31:1423–9 e2.

[66] Kim JK, Lee KS, Lee DK, Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice[J]. Exp Mol Med, 2014, 46(12): e127

[67] Parafati M, Lascala A, Morittu VM, Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome[J]. J Nutr Biochem, 2015, 26(9): 938–948.

[68] Shibata M, Yoshimura K, Furuya N, The MAP1–LC3 conjugation system is involved in lipid droplet formation[J]. Biochem Biophys Res Commun, 2009, 382(2): 419–423.

[69] Dupont N, Chauhan S, Arko-Mensah J, Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis[J]. Curr Biol, 2014, 24(6): 609–620.

[70] Volmer R, Ron D. Lipid-dependent regulation of the unfolded protein response[J]. Curr Opin Cell Biol, 2015, 33: 67–73.

[71] Choi YJ, Shin HS, Choi HS, Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes[J]. Lab Invest, 2014, 94(10): 1114–1125.

[72] Peterson TR, Sengupta SS, Harris TE, mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway[J]. Cell, 2011, 146(3): 408–420.

[73] Zhang P, Verity MA, Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle[J]. Cell Metab, 2014, 20(2): 267–279.

[74] Sapp V, Gaffney L, EauClaire SF, EauClaire SF, Matthews RP. Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition[J]. Hepatology, 2014, 60(5): 1581–1592.

[75] Altomonte J, Cong L, Harbaran S, Foxo1 mediates insulin action on apoC-III and triglyceride metabolism[J]. J Clin Invest, 2004, 114(10): 1493–1503

[76] Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c[J]. Diabetes Obes Metab, 2010, 12(Suppl 2): 83–92.

[77] Kamagate A, Qu S, Perdomo G, FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice[J]. J Clin Invest, 2008, 118: 2347–2364.

[78] Wu X, Chen K, Williams KJ. The role of pathway-selective insulin resistance and responsiveness in diabetic dyslipoproteinemia[J]. Curr Opin Lipidol, 2012, 23(4): 334–344.

[79] Yao Z, Wang Y. Apolipoprotein C–III and hepatic triglyceride-rich lipoprotein production[J]. Curr Opin Lipidol, 2012, 23(3): 206–212.

[80] Promrat K, Kleiner DE, Niemeier HM, Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis[J]. Hepatology, 2010, 51(1): 121–129.

[81] Lincoff AM, Wolski K, Nicholls SJ, Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials[J]. JAMA, 2007, 298(10): 1180–1188.

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