Nonalcoholic Fatty Liver Disease. Lipids and Insulin Resistance.

Clinics in Liver Disease

Volumn 20, Issue 2, 2016, Pages 245-262

  Berk, Paul D ^a   Verna, Elizabeth C ^a  

^a Columbia College of Physicians and Surgeons Columbia University Medical Center ^*  (United States)

Author keywords

Facilitated transport; Leptin; Lipotoxicity; Spexin; Weight regain

Indexed keywords

ASPARTATE AMINOTRANSFERASE; CAVEOLIN 1; CD36 ANTIGEN; FATTY ACID BINDING PROTEIN; INSULIN; LEPTIN; LIPOPROTEIN LIPASE; LONG CHAIN FATTY ACID; MESSENGER RNA; PEPTIDES AND PROTEINS; PHOSPHOLIPASE A2; TRIACYLGLYCEROL; C12ORF39 PROTEIN, HUMAN; FATTY ACID; PEPTIDE HORMONE;

ADIPOCYTE; BODY MASS; CARDIOMYOPATHY; COHORT ANALYSIS; COMORBIDITY; DISEASE COURSE; DOWN REGULATION; ENZYME ACTIVITY; FATTY ACID TRANSPORT; GASTRIC BANDING; GLUCOSE TRANSPORT; HEART MUSCLE CELL; HUMAN; INSULIN RESISTANCE; LIPOLYSIS; LIPOTOXICITY; LIVER CELL; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PATHOGENESIS; POSTOPERATIVE PERIOD; REVIEW; ROUX Y ANASTOMOSIS; WEIGHT GAIN; WEIGHT REDUCTION; WEIGHT REGAIN; ANIMAL; DISEASE MODEL; GENETICS; METABOLISM;

ANIMALS; DISEASE MODELS, ANIMAL; FATTY ACIDS; HUMANS; INSULIN RESISTANCE; LEPTIN; NON-ALCOHOLIC FATTY LIVER DISEASE; OBESITY; PEPTIDE HORMONES; TRIGLYCERIDES;

EID: 84958576401     PISSN: 10893261     EISSN: 15578224     Source Type: Journal    
DOI: 10.1016/j.cld.2015.10.007     Document Type: Review

References (113)

1. Ludwig J., Viggiano T.R., McGill D.B., et al. Nonalcoholic steatohepatitis: Mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980, 55:434-438.
2. Diehl A.M., Goodman Z., Ishak K.G. Alcohol-like liver disease in non-alcoholics. Gastroenterology 1988, 95:1056-1062.
3. Clain D.J., Lefkowitch J.H. Fatty liver disease in morbid obesity. Gastroenterol Clin North Am 1987, 16:239-252.
4. Chalasani N., Younossi Z., Lavine J.E., American Gastroenterological Association, American Association for the Study of Liver Diseases, American College of Gastroenterology, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012, 142(7):1592-1609.
5. Burt A.D., Lackner C., Tiniakos D.G. Diagnosis and assessment of NAFLD: definitions and histopathological classification. Semin Liver Dis 2015, 35(3):207-220.
6. Vanni E., Bugianesi E., Kotronen A., et al. From the metabolic syndrome to NAFLD or vice versa. Dig Liver Dis 2010, 42(5):320-330.
7. Satapathy S.K., Sanyal A.J. Epidemiology and natural history of non-alcoholic fatty liver disease. Semin Liver Dis 2015, 35(3):221-235.
8. Vanni E., Marengo A., Mezzabotta L., et al. Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander. Semin Liver Dis 2015, 35(3):236-249.
9. Moore J.B. Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc 2010, 69:211-220.
10. Farrell G.C., Wong V.W., Chitturi S. NAFLD in Asia-as common and as important as in the West. Nat Rev Gastroenterol Hepatol 2013, 10:307-318.
11. Loomba R., Sanyal A.J. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013, 10:686-690.
12. Speliotes E.K., Yerges-Armstrong L.M., Wu J., et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011, 7(3):e1001324.
13. Anstee Q.M., Day C.P. The genetics of nonalcoholic fatty liver disease; spotlight on PNPLA3 & TM6SF2. Semin Liver Dis 2015, 35(5):270-290.
14. Powell E.E., Cooksley W.G., Hanson R., et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990, 11(1):74-80.
15. Teli M.R., James O.F., Burt A.D., et al. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995, 22(6):1714-1719.
16. Harrison S.A., Torgerson S., Hayashi P.H. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003, 98:2042-2047.
17. Fassio E., Alvarez E., Dominguez N., et al. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004, 40(4):820-826.
18. Adams L.A., Sanderson S., Lindor K., et al. The histological course of nonalcoholic fatty liver: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005, 42(1):132-138.
19. Ekstedt M., Franzén L.E., Mathiesen U.L., et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44(4):865-873.
20. Merriman R.B., Ferrell L.D., Patti M.G., et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006, 44(4):874-880.
21. Wong V.W., Wong G.L., Choi P.C., et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010, 59(7):969-974.
22. Pais R., Charlotte F., Fedchuk L., LIDO Study Group, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013, 59(3):550-556.
23. McPherson S., Hardy T., Henderson E., et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015, 62(5):1148-1155.
24. Singh S., Allen A.M., Wang Z., et al. Fibrosis progression in nonalcoholic fatty liver vs. nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015, 13(4):643-654.
25. Harrison S.A. Nonalcoholic fatty liver disease and fibrosis progression: the Good, the Bad, and the Unknown. Clin Gastroenterol Hepatol 2015, 13(4):655-657.
26. Yilmaz Y. Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions?. Aliment Pharmacol Ther 2012, 36:815-823.
27. Fielding C., Angulo P. Hepatic steatosis and steatohepatitis: are they really two distinct entities?. Curr Hepatol Rep 2014, 13(2):151-158.
28. Ge F., Zhou S., Hu C., et al. Increased insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling, but not in those lacking leptin or its receptor. Am J Physiol Gastrointest Liver Physiol 2010, 299:855-866.
29. Ge F., Lobdell H., Zhou S., et al. Digital analysis of hepatic sections accurately quantitates triglycerides and selected properties of lipid droplets. Exp Biol Med 2010, 235(11):1282-1286.
30. Ge F., Hu C., Hyodo E., et al. Cardiomyocyte triglyceride accumulation and reduced ventricular function occurs in mice with obesity and hepatic steatosis from many causes and reflects increased long chain fatty acid uptake and de novo fatty acid synthesis. J Obes 2012, 2012:205648.
31. Stremmel W., Berk P.D. Hepatocellular influx of [14C]oleate reflects membrane transport rather than intracellular metabolism or binding. Proc Natl Acad Sci U S A 1986, 83(10):3086-3090.
32. Schwieterman W., Sorrentino D., Potter B.J., et al. Uptake of oleate by isolated rat adipocytes is mediated by a 40-kDa plasma membrane fatty acid binding protein closely related to that in liver and gut. Proc Natl Acad Sci U S A 1988, 85(2):359-363.
33. Stump D.D., Nunes R.M., Sorrentino D., et al. Characteristics of oleate binding to liver plasma membranes and its uptake by isolated hepatocytes. J Hepatol 1992, 16(3):304-315.
34. Berk P.D., Stump D.D. Mechanisms of cellular uptake of long chain free fatty acids. Mol Cell Biochem 1999, 192(1-2):17-31.
35. Stump D.D., Fan X., Berk P.D. Oleic acid uptake and binding by rat adipocytes define dual pathways for cellular fatty acid uptake. J Lipid Res 2001, 42(4):509-520.
36. Schmider W., Fahr A., Blum H.E., et al. Transport of heptafluorostearate across model membranes: membrane transport of long-chain fatty acid anions. J Lipid Res 2000, 41(5):775-787.
37. Abumrad N.A., Park J.H., Park C.R. Permeation of long-chain fatty acid into adipocytes: kinetics, specificity, and evidence for involvement of a membrane protein. J Biol Chem 1984, 259(14):8945-8953.
38. Weisiger R.A., Fitz J.G., Scharschmidt B.F. Hepatic oleate uptake: electrochemical driving forces in intact rat liver. J Clin Invest 1989, 83(2):411-420.
39. Glatz J.F., van Nieuwenhoven F.A., Luiken J.J., et al. Role of membrane-associated and cytoplasmic fatty acid-binding proteins in cellular fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids 1997, 57(4-5):373-378.
40. Luiken J.J., Glatz J.F., Bonen A. Fatty acid transport proteins facilitate fatty acid uptake in skeletal muscle. Can J Appl Physiol 2000, 25(5):333-352.
41. Kampf J.P., Kleinfeld A.M. Fatty acid transport in adipocytes monitored by imaging intracellular free fatty acid levels. J Biol Chem 2004, 279(34):35775-35780.
42. Kleinfeld A.M., Kampf J.P., Lechene C. Transport of 13C-oleate in adipocytes measured using multi imaging mass spectrometry. J Am Soc Mass Spectrom 2004, 15(11):1572-1580.
43. Stremmel W., Strohmeyer G., Borchard F., et al. Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes. Proc Natl Acad Sci U S A 1985, 82(1):4-8.
44. Bradbury M.W., Berk P.D. Cellular uptake of long chain free fatty acids: the structure and function of plasma membrane fatty acid binding protein. Adv Mol Cell Biol 2004, 33:47-81.
45. Abumrad N.A., el-Maghrabi M.R., Amri E.Z., et al. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation: homology with human CD36. J Biol Chem 1993, 268(24):17665-17668.
46. Schaffer J.E., Lodish H.F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 1994, 79(3):427-436.
47. Stahl A., Gimeno R.E., Tartaglia L.A., et al. Fatty acid transport proteins: a current view of a growing family. Trends Endocrinol Metab 2001, 12(6):266-273.
48. Trigatti B.L., Anderson R.G., Gerber G.E. Identification of caveolin-1 as a fatty acid binding protein. Biochem Biophys Res Commun 1999, 255(1):34-39.
49. Pohl J., Ring A., Stremmel W. Uptake of long-chain fatty acids in HepG2 cells involves caveolae: analysis of a novel pathway. J Lipid Res 2002, 43(9):1390-1399.
50. Kampf J.P., Parmley D., Kleinfeld A.M. Free fatty acid transport across adipocytes is mediated by an unknown membrane protein pump. Am J Physiol Endocrinol Metab 2007, 293(5):E1207-E1214.
51. Kampf J.P., Kleinfeld A.M. Is membrane transport of FFA mediated by lipid, protein, or both? An unknown protein mediates free fatty acid transport across the adipocyte plasma membrane. Physiology (Bethesda) 2007, 22:7-14.
52. Berk P.D., Wada H., Horio Y., et al. Plasma membrane fatty acid-binding protein and mitochondrial glutamic-oxaloacetic transaminase of rat liver are related. Proc Natl Acad Sci U S A 1990, 87(9):3484-3488.
53. Bradbury M.W., Stump D., Guarnieri F., et al. Molecular modeling and functional confirmation of a predicted fatty acid binding site in mitochondrial aspartate aminotransferase. J Mol Biol 2011, 412(3):412-422.
54. Watkins P.A. Fatty acid activation. Prog Lipid Res 1997, 36:55-83.
55. Digel M., Ehehalt R., Stremmel W., et al. Acyl-CoA synthetases: fatty acid uptake and metabolic channeling. Mol Cell Biochem 2009, 326:23-28.
56. Hall A.M., Smith A.J., Bernlohr D.A. Characterization of the acyl-CoA synthetase activity of purified murine fatty acid transport protein 1. J Biol Chem 2003, 278:43008-43013.
57. Hall A.M., Wiczer B.M., Herrmann T., et al. Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl CoA synthetase activities in tissues from FATP4 null mice. J Biol Chem 2005, 280:11948-11954.
58. Black P.N., DiRusso C.C. Transmembrane movement of exogenous long-chain fatty acids: proteins, enzymes, and vectorial esterification. Microbiol Mol Biol Rev 2003, 67:4544-4572.
59. Kalant D., Cianflone K. Regulation of fatty acid transport. Curr Opin Lipidol 2004, 15:309-314.
60. Stremmel W., Staffer S., Wannhoff A., et al. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacologic modulation: implications for nonalcoholic steatohepatitis. FASEB J 2014, 28:3159-3170.
61. Berk P.D., Zhou S.L., Kiang C.L., et al. Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of Zucker rats with genetic obesity and non-insulin-dependent diabetes mellitus. J Biol Chem 1997, 272(13):8830-8835.
62. Chua S.C., Chung W.K., Wu-Peng X.S., et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996, 271(5251):994-996.
63. Wang B., Charukeshi-Chandrasekera P., Pippin J.J. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev 2014, 10:131-145.
64. Sanches S.C., Ramalho L.N., Augusto M.J., et al. Nonalcoholic steatohepatitis: a search for factual animal models. Biomed Res Int 2015, 2015:574832.
65. Berk P.D., Zhou S., Kiang C., et al. Selective up-regulation of fatty acid uptake by adipocytes characterizes both genetic and diet-induced obesity in rodents. J Biol Chem 1999, 274(40):28626-28631.
66. Petrescu O., Fan X., Gentileschi P., et al. Long-chain fatty acid uptake is upregulated in omental adipocytes from patients undergoing bariatric surgery for obesity. Int J Obes (Lond) 2005, 29(2):196-203.
67. Ge F., Walewski J.L., Torghabeh M.H., et al. Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss. Obesity (Silver Spring) 2016, 24(1):113-122.
68. Fan X., Bradbury M.W., Berk P.D. Leptin and insulin modulate nutrient partitioning and weight loss in ob/ob mice through regulation of long-chain fatty acid uptake by adipocytes. J Nutr 2003, 133(9):2707-2715.
69. Vacca M., Allison M., Griffin J.L., et al. Fatty acid and glucose sensors in hepatic lipid metabolism: implications for NAFLD. Semin Liver Dis 2015, 35(5):250-261.
70. Schaffer J.E. Lipotoxicity: when tissues overeat. Curr Opin Lipidol 2003, 14:281-287.
71. Bradbury M.W., Berk P.D. Lipid metabolism in hepatic steatosis. Clin Liver Dis 2004, 8(3):639-671.
72. Lee G.H., Proenca R., Montez J.M., et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996, 379(6566):632-635.
73. Phillips M.S., Liu Q., Hammond H.A., et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996, 13(1):18-19.
74. Zhang Y., Proenca R., Maffei M., et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372(6505):425-432.
75. Maclean P.S., Bergouignan A., Cornier M.A., et al. Biology's response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol 2011, 301(3):R581-R600.
76. Blomain E.S., Dirhan D.A., Valentino M.A., et al. Mechanisms of weight regain following weight loss. ISRN Obes 2013, 2013:210524.
77. Greenway F.L. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond) 2015, 39(8):1188-1196.
78. Courcoulas A.P., Christian N.J., Belle S.H., et al. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA 2013, 310(22):2416-2425. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium.
79. Lee Y., Wang M.Y., Kakuma T., et al. Liporegulation in diet induced obesity: the antisteatotic role of hyperleptinemia. J Biol Chem 2001, 276(8):5629-5635.
80. Unger R.H. Lipotoxic diseases. Annu Rev Med 2002, 53:319-336.
81. Unger R.H. The physiology of cellular liporegulation. Annu Rev Physiol 2003, 65:333-347.
82. Halaas J.L., Gajiwala K.S., Maffei M., et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995, 269(5223):543-546.
83. Pelleymounter M.A., Cullen M.J., Baker M.B., et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269(5223):540-543.
84. Campfield L.A., Smith F.J., Guisez Y., et al. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995, 269(5223):546-549.
85. Remesar X., Rafecas I., Fernandez-Lopez J.A., et al. Is leptin an insulin counter-regulatory hormone?. FEBS Lett 1997, 402(1):9-11.
86. Myers M.G., Cowley M.A., Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008, 70:537-556.
87. Oh-I S., Shimizu H., Sato T., et al. Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain. Cell Metab 2005, 1(5):331-341.
88. Listenberger L.L., Ory D.S., Schaffer J.E. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem 2001, 276(18):14890-14895.
89. Unger R.H., Orci L. Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J 2001, 15(2):312-321.
90. Unger R.H. Minireview: weapons of lean body mass destruction-the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003, 144(12):5159-5165.
91. Shimomura I., Hammer R.E., Ikemoto S., et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401(6748):73-76.
92. Mirabeau O., Perlas E., Severini C., et al. Identification of novel peptide hormones in the human proteome by hidden Markov model screening. Genome Res 2007, 17:320-327.
93. Walewski J.L., Ge F., Lobdell H., et al. Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity. Obesity (Silver Spring) 2014, 22(7):1643-1652.
94. Haynes P., Liangpunsakul S., Chalasani N. Nonalcoholic fatty liver disease in individuals with severe obesity. Clin Liver Dis 2004, 8(3):535-547.
95. Zhou S.L., Gordon R.E., Bradbury M., et al. Ethanol up-regulates fatty acid uptake and plasma membrane expression and export of mitochondrial aspartate aminotransferase in HepG2 cells. Hepatology 1998, 27(4):1064-1074.
96. Berk P.D., Zhou S., Bradbury M.W. Increased hepatocellular uptake of long chain fatty acids occurs by different mechanisms in fatty livers due to obesity or excess ethanol use, contributing to development of steatohepatitis in both settings. Trans Am Clin Climatol Assoc 2005, 116:335-344.
97. Yeh M.M., Brunt E.M. Pathological features of fatty liver disease. Gastroenterol 2014, 147(4):754-764.
98. Kleiner D.E., Berk P.D., Hsu J.Y., et al. Hepatic pathology among patients without known liver disease undergoing bariatric surgery: observations and a perspective from the Longitudinal Assessment of Bariatric Surgery (LABS) study. Semin Liver Dis 2014, 34(1):98-107. LABS Consortium.
99. Neuschwander-Tetri B.A., Clark J.M., Bass N.M., NASH Clinical Research Network, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010, 52(3):913-924.
100. Day C.P., James O.F. Steatohepatitis: a tale of two "hits"?. Gastroenterology 1998, 114(4):842-845.
101. Charlton M. Noninvasive indices of fibrosis in NAFLD: starting to think about a three-hit (at least) phenomenon. Am J Gastroenterol 2007, 102(2):409-411.
102. McCullough A.J. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006, 40(3 Suppl 1):S17-S29.
103. Mantena S.K., King A.L., Andringa K.K., et al. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med 2008, 44(7):1259-1272.
104. Mahli H., Gores G. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008, 28(4):360-369.
105. Diehl A. Mechanisms of disease and progression in NAFLD. Semin Liver Dis 2008, 28(4):370-379.
106. Bugianesi E., Leone N., Vanni E., et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002, 123(1):134-140.
107. Pocha C., Kolly P., Dufour J.-F. Nonalcoholic fatty liver disease-related hepatocellular carcinoma - a problem of growing magnitude. Semin Liver Dis 2015, 35(3):304-317.
108. Torres D.M., Harrison S.A. Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: fertile soil. Semin Liver Dis 2012, 32(1):30-38.
109. Ponziani F.R., Pecere S., Gasbarrini A., et al. Physiology and pathophysiology of liver lipid metabolism. Expert Rev Gastroenterol Hepatol 2015, 9(8):1055-1067.
110. Nguyen V., George J. Nonalcoholic fatty liver disease management: dietary and lifestyle modifications. Semin Liver Dis 2015, 35(3):318-337.
111. Gawrieh S., Chalasani N. Pharmacotherapy for non-alcoholic fatty liver disease. Semin Liver Dis 2015, 35(3):338-348.
112. Filozof C., Goldstein B.J., Williams R.N., et al. Non-alcoholic steatohepatitis: limited available treatment options but promising drugs in development and recent progress towards a regulatory approval pathway. Drugs 2015, 75(12):1373-1392.
113. Takahashi Y., Sugimoto K., Inui H., et al. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2015, 21(13):3777-3785.