842
Views
10
CrossRef citations to date
0
Altmetric
Review

The molecular basis for current targets of NASH therapies

&
Pages 151-161 | Received 07 Dec 2019, Accepted 08 Dec 2019, Published online: 18 Dec 2019

References

  • Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol. 2018;68:362–375.
  • Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–353.
  • Cheung A, Neuschwander-Tetri BA, Kleiner DE, et al. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum. Hepatology. 2019;70:1841–1855.
  • Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–788.
  • Fuchs M, Sanyal AJ. Lipotoxicity in NASH. J Hepatol. 2012;56:291–293.
  • Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–725.
  • Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150:1769–1777.
  • Hirsova P, Ibrahim SH, Gores GJ, et al. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res. 2016;57:1758–1770.
  • Mota M, Banini BA, Cazanave SC, et al. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism. 2016;65:1049–1061.
  • Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68:280–295.
  • Musso G, Cassader M, Paschetta E, et al. Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis. Gastroenterology. 2018;155:282–302.
  • Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol. 2013;10:676–685.
  • Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016;15:249–274.
  • Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–922.
  • Dibba P, Li AA, Perumpail BJ, et al. Emerging therapeutic targets and experimental drugs for the treatment of NAFLD. Diseases. 2018;6:83.
  • Xu B, Xie X. Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci. 2016;17:282–292.
  • Farr OM, Li C-SR, Mantzoros CS. Central nervous system regulation of eating: insights from human brain imaging. Metabolism. 2016;65:699–713.
  • Comeras LB, Herzog H, Tasan RO. Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y. Ann N Y Acad Sci. 2019;1455:59–80.
  • Anastasiou CA, Karfopoulou E, Yannakoulia M. Weight regaining: from statistics and behaviors to physiology and metabolism. Metabolism. 2015;64:1395–1407.
  • BonDurant LD, Potthoff MJ. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu Rev Nutr. 2018;38:173–196.
  • Kliewer SA, Mangelsdorf DJ. A dozen years of discovery: insights into the physiology and pharmacology of FGF21. Cell Metab. 2019;29:246–253.
  • Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2019;392:2705–2717.
  • Steinert RE, Feinle-Bisset C, Asarian L, et al. Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev. 2017;97:411–463.
  • English WJ, Williams DB. Metabolic and bariatric surgery: an effective treatment option for obesity and cardiovascular disease. Prog Cardiovasc Dis. 2018;61:253–269.
  • Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–388.
  • Bazerbachi F, Vargas Valls EJ, Abu Dayyeh BK. Recent clinical results of endoscopic bariatric therapies as an obesity intervention. Clin Endosc. 2017;50:42–50.
  • Harrison SA, Fincke C, Helinski D, et al. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther. 2004;20:623–628.
  • Zelber-Sagi S, Kessler A, Brazowsky E, et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:639–644.
  • Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: a common comorbidity associated with severe complications. Diabetes Metab. 2019;45:213–223.
  • Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition. Diabetes Obes Metab. 2016;18:125–134.
  • Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial). Diabetes Care. 2018;41:1801–1808.
  • Zelber-Sagi S, Godos J, Salomone F. Lifestyle changes for the treatment of nonalcoholic fatty liver disease: a review of observational studies and intervention trials. Therap Adv Gastroenterol. 2016;9:392–407.
  • Kenneally S, Sier JH, Moore JB. Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review. BMJ Open Gastroenterol. 2017;4:e000139.
  • Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–846.
  • Winn NC, Liu Y, Rector RS, et al. Energy-matched moderate and high intensity exercise training improves nonalcoholic fatty liver disease risk independent of changes in body mass or abdominal adiposity - a randomized trial. Metabolism. 2018;78:128–140.
  • Gerber L, Otgonsuren M, Mishra A, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical activity: a population-based study. Aliment Pharmacol Ther. 2012;36:772–781.
  • Booth FW, Roberts CK, Thyfault JP, et al. Role of inactivity in chronic diseases: evolutionary insight and pathophysiological mechanisms. Physiol Rev. 2017;97:1351–1402.
  • Schäfer S, Kantartzis K, Machann J, et al. Lifestyle intervention in individuals with normal versus impaired glucose tolerance. Eur J Clin Invest. 2007;37:535–543.
  • Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18:e12880.
  • Chouchani ET, Kazak L, Spiegelman BM. New advances in adaptive thermogenesis: UCP1 and beyond. Cell Metab. 2019;29:27–37.
  • Cohen P, Spiegelman BM. Brown and beige fat: molecular parts of a thermogenic machine. Diabetes. 2015;64:2346–2351.
  • Ruiz JR, Martinez-Tellez B, Sanchez-Delgado G, et al. Role of human brown fat in obesity, metabolism and cardiovascular disease: strategies to turn up the heat. Prog Cardiovasc Dis. 2018;61:232–245.
  • Green AL, Bagci U, Hussein S, et al. Brown adipose tissue detected by PET/CT imaging is associated with less central obesity. Nucl Med Commun. 2017;38:629–635.
  • Bouter KEC, Bakker GJ, Levin E, et al. Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects. Clin Transl Gastroenterol. 2018;9:155.
  • BonDurant LD, Ameka M, Naber MC, et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 2017;25:935–944.
  • Sonoda J, Chen MZ, Baruch A. FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases. Hormone Mol Biol Clin Invest. 2017;30:19.
  • Schaap FG, Trauner M, Jansen PLM. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11:55–67.
  • van Nierop FS, Scheltema MJ, Eggink HM, et al. Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol. 2017;5:224–233.
  • Al-Dury S, Marschall H-U. Ileal bile acid transporter inhibition for the treatment of chronic constipation, cholestatic pruritus, and NASH. Front Pharmacol. 2018;9:931.
  • Arab JP, Karpen SJ, Dawson PA, et al. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology. 2017;65:350–362.
  • Benoit B, Meugnier E, Castelli M, et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med. 2017;23:990.
  • Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018;391:1174–1185.
  • Harrison SA, Rossi SJ, Paredes AH, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology. 2019. DOI:10.1002/hep.30590
  • Schneider JG, Nadeau JH. Turn up the heat: circulating serotonin tunes our internal heating system. Cell Metab. 2015;21:156–158.
  • Choi W, Namkung J, Hwang I, et al. Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nat Commun. 2018;9:4824.
  • Beiroa D, Imbernon M, Gallego R, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014;63:3346–3358.
  • Cusi K. Incretin-based therapies for the management of nonalcoholic fatty liver disease in patients with type 2 diabetes. Hepatology. 2019;69:2318–2322.
  • Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–690.
  • Sloop KW, Briere DA, Emmerson PJ, et al. Beyond glucagon-like peptide-1: is G-protein coupled receptor polypharmacology the path forward to treating metabolic diseases? ACS Pharmacol Transl Sci. 2018;1:3–11.
  • Dushay J, Chui PC, Gopalakrishnan GS, et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010;139:456–463.
  • Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.
  • Bril F, Kalavalapalli S, Clark VC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16:558–566.
  • Guilherme A, Virbasius JV, Puri V, et al. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–377.
  • Alkhouri N, Gornicka A, Berk MP, et al. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem. 2010;285:3428–3438.
  • Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol. 2008;14:22–28.
  • Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–1159.
  • Mann JP, Anstee QM. NAFLD: PNPLA3 and obesity: a synergistic relationship in NAFLD. Nat Rev Gastroenterol Hepatol. 2017;14:506–507.
  • Pingitore P, Romeo S. The role of PNPLA3 in health and disease. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864:900–906.
  • BasuRay S, Wang Y, Smagris E, et al. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A. 2019;116:9521–9526.
  • Taub R, Chiang E, Chabot-Blanchet M, et al. Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis. 2013;230:373–380.
  • Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012–2024.
  • Sinha RA, Bruinstroop E, Singh BK, et al. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists. Thyroid. 2019;29:1173–1191.
  • McCommis KS, Finck BN. Treating hepatic steatosis and fibrosis by modulating mitochondrial pyruvate metabolism. Cell Mol Gastroenterol Hepatol. 2019;7:275–284.
  • Colca JR, McDonald WG, McCommis KS, et al. Treating fatty liver disease by modulating mitochondrial pyruvate metabolism. Hepatol Commun. 2017;1:193–197.
  • Harrison SA, Alkhouri N, Davison BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2019. DOI:10.1016/j.jhep.2019.10.023
  • Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351.
  • Sepe V, Distrutti E, Fiorucci S, et al. Farnesoid X receptor modulators 2014-present: a patent review. Expert Opin. 2018;28:351–364.
  • Esler WP, Bence KK. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol Gastroenterol Hepatol. 2019;8:247–267.
  • Fiorucci S, Rizzo G, Donini A, et al. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med. 2007;13:298–309.
  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.
  • Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019. DOI:10.1016/S0140-6736(19)33041-7
  • Pinkosky SL, Groot PHE, Lalwani ND, et al. Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders. Trends Mol Med. 2017;23:1047–1063.
  • Stiede K, Miao W, Blanchette HS, et al. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology. 2017;66:324–334.
  • Loomba R, Kayali Z, Noureddin M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155:1463–1473.
  • Ratziu V, Ladron-De-Guevara L, Safadi R, et al. One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with NASH (abstract). Hepatology. 2018;68:1448A–1449A.
  • Hoang SA, Oseini A, Feaver RE, et al. Gene expression predicts histological severity and reveals distinct molecular profiles of nonalcoholic fatty liver disease. Sci Rep. 2019;9:12541.
  • Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389–1397.
  • Lambert JE, Ramos-Roman MA, Browning JD, et al. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–735.
  • Stremmel W, Staffer S, Wannhoff A, et al. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis. Faseb J. 2014;28:3159–3170.
  • Lebeaupin C, Vallée D, Hazari Y, et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927–947.
  • Traussnigg S, Schattenberg JM, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol. 2019;4:781–793.
  • Hardy T, Oakley F, Anstee QM, et al. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu Rev Pathol. 2016;11:451–496.
  • Spahis S, Delvin E, Borys J-M LE. Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis. Antioxid Redox Signal. 2017;26:519–541.
  • Masarone M, Rosato V, Dallio M, et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longevity. 2018;2018:9547613.
  • Risérus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes. 2008;57:332–339.
  • Abdelmalek MF, Sanderson SO, Angulo P, et al. Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology. 2009;50:1818–1826.
  • Schwimmer JB, Lavine JE, Wilson LA, et al. In children with nonalcoholic fatty liver disease, cysteamine bitartrate delayed release improves liver enzymes but does not reduce disease activity scores. Gastroenterology. 2016;151:1141–1154 e1149.
  • Forman HJ, Fukuto JM, Torres M. Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol. 2004;287:C246–256.
  • Lei XG, Zhu JH, Cheng WH, et al. Paradoxical roles of antioxidant enzymes: basic mechanisms and health implications. Physiol Rev. 2016;96:307–364.
  • Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 2012;55:1711–1721.
  • Tay EY-X, Teoh Y-L, Yeo MS-W. Hedgehog pathway inhibitors and their utility in basal cell carcinoma: a comprehensive review of current evidence. Dermatol Ther (Heidelb). 2019;9:33–49.
  • Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol. 2015;12:387–400.
  • Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2018;67:549–559.
  • Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67:1754–1767.
  • Satapathy SK, Garg S, Chauhan R, et al. Beneficial effects of tumor necrosis factor-α inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1946–1952.
  • Satapathy SK, Sakhuja P, Malhotra V, et al. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:634–638.
  • Van Wagner LB, Koppe SW, Brunt EM, et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011;10:277–286.
  • Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol. 2015;1:17–27.
  • Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184.
  • Kim JY, Garcia-Carbonell R, Yamachika S, et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell. 2018;175:133–145.e115.
  • Ratziu V, Sheikh MY, Sanyal AJ, et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology. 2012;55:419–428.
  • Frenette CT, Morelli G, Shiffman ML, et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol. 2019;17:774–783.
  • Shiffman M, Freilich B, Vuppalanchi R, et al. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2019;49:64–73.
  • Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411.
  • Harrison SA, Abdelmalek MF, Caldwell S, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology. 2018;155:1140–1153.
  • Romero A, Gabius H-J. Galectin-3: is this member of a large family of multifunctional lectins (already) a therapeutic target? Expert Opin Ther Targets. 2019;23:819–828.
  • Dyson J, Jaques B, Chattopadyhay D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60:110–117.
  • Mittal S, El-Serag HB, Sada YH, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14:124–131.
  • Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827–838.
  • Hirsova P, Ibrahim A, Malhi H, et al. Hepatocyte lethal and nonlethal lipotoxic injury. In: Ding W-X, Yin X-M, editors. Cellular injury in liver diseases. Switzerland: Springer Nature; 2017. p. 105–117.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.