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Review

Emerging therapeutic targets for NASH: key innovations at the preclinical level

ORCID Icon &
Pages 175-186 | Received 13 Jan 2020, Accepted 09 Feb 2020, Published online: 13 Feb 2020

References

  • NCD-RisC. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet. 2017;390:2627–2642.
  • O’Neill S, O’Driscoll L Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 2015;16:1–12.
  • Kotronen A, Westerbacka J, Bergholm R, et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92:3490–3497.
  • Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20.
  • EASL, EASD, EASO. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.
  • Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.
  • Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97 e10.
  • Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–378.e5.
  • Konerman MA, Jones JC, Harrison SA Pharmacotherapy for NASH: current and emerging. J Hepatol. . 2018;68:362–375.
  • 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;394:2184–2196.
  • Siddiqui MS, Van Natta ML, Connelly MA, et al. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol 2020;72:25–33.
  • Pockros PJ, Fuchs M, Freilich B, et al. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int. 2019;39:2082–2093.
  • Arab JP, Arrese M, Trauner M Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol Mech Dis 2018;13:321–350.
  • Khan RS, Bril F, Cusi K, et al. Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology. 2019.70:711–724.
  • Marra F, Svegliati-Baroni G Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68:280–295.
  • Caballero F, Fernandez A, De Lacy AM, et al. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol. 2009;50:789–796.
  • 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.
  • Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–1075.
  • Sanders FWB, Griffin JL De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev 2016;91:452–468.
  • Esquejo RM, Salatto CT, Delmore J, et al. Activation of liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine. 2018;31:122–132.
  • 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.
  • Gao YS, Qian MY, Wei QQ, et al. WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice. Acta Pharmacol Sin. 2019.0:1-12.
  • Harriman G, Greenwood J, Bhat S, et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci 2016;113:E1796.
  • 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.e6.
  • JS V L, Ghoshal S, DePeralta DK, et al. Inhibition of Acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 2019;29:174–182 e5.
  • Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 2017;26:394–406 e6.
  • Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, paral. J Am Coll Cardiol. 2013;62:1154–1162.
  • Day EA, Ford RJ, Steinberg GR. AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol. Metab. 2017;28:545–560.
  • Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–1971.
  • Lim JS, Mietus-Snyder M, Valente A, et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010;7:251–264.
  • Petersen MC, Vatner DF, Shulman GI Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13:572–587.
  • Miller CO, Yang X, Lu K, et al. Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. Am J Physiol Endocrinol Metab. 2018;315:E386–E393.
  • Softic S, Meyer JG, Wang G-X, et al. Dietary sugars alter hepatic fatty acid oxidation via transcriptional and post-translational modifications of mitochondrial proteins. Cell Metab. 2019;30:735–753.e4.
  • Softic S, Gupta MK, Wang G-X, et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 2017;127:4059–4074.
  • Tran C. Inborn errors of fructose metabolism. What can we learn from them? Nutrients. 2017;9:356
  • Calle R, Bergman A, Somayaji V, et al. PS-110-Ketohexokinase inhibitor PF-06835919 administered for 6 weeks reduces whole liver fat as measured by magnetic resonance imaging-proton density fat fraction in subjects with non-alcoholic fatty liver disease. J Hepatol 2019;70:e69–e70.
  • Lebeaupin C, Vallee D, Hazari Y, et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69:927–947.
  • 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 e15.
  • Lebeaupin C, Vallee D, Rousseau D, et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology. 2018;68:515–532.
  • Shan B, Wang X, Wu Y, et al. The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017;18:519–529.
  • Tufanli O, Telkoparan Akillilar P, Acosta-Alvear D, et al. Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc Natl Acad Sci U S A. 2017;114:E1395–E1404.
  • Zhang K, Wang S, Malhotra J, et al. The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. Embo J. 2011;30:1357–1375.
  • Upton J-P, Wang L, Han D, et al. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science. 2012;338:818–822.
  • Sandow JJ, Dorstyn L, O’Reilly LA, et al. ER stress does not cause upregulation and activation of caspase-2 to initiate apoptosis. Cell Death Differ. 2014;21:475–480.
  • Krumschnabel G, Sohm B, Bock F, et al. The enigma of caspase-2: the laymen’s view. Cell Death Differ. 2009;16:195–207.
  • Szabo G, Petrasek J Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol. 2015;12:387–400.
  • Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477–489.
  • Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–185.
  • Wree A, Eguchi A, McGeough MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59:898–910.
  • Csak T, Ganz M, Pespisa J, et al. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 2011;54:133–144.
  • Mridha AR, Wree A, Robertson AAB, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017;66:1037–1046.
  • Wei Q, Guo P, Mu K, et al. Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome. Lab Invest 2015;95:804–816.
  • Dabbagh K, Steven Dodson G, Yamamoto L, et al. PS-111 - Preclinical and first-in human development of SGM-1019, a first-in-class novel small molecule modulator of inflammasome activity for the treatment of nonalcoholic steatohepatitis (NASH). J Hepatol 2018;68:S60.
  • Mullard A NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Discov. 2019;18:405–407.
  • Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 2018;17:588–606.
  • Qiu S, Liu J, Xing F ‘Hints’ in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death. Cell Death Differ. 2017;24:588–596.
  • Zhaolin Z, Guohua L, Shiyuan W, et al. Role of pyroptosis in cardiovascular disease. Cell Prolif. 2019;52:e12563.
  • Man SM, Karki R, Kanneganti T-D Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61–75.
  • Khanova E, Wu R, Wang W, et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology. 2018;67:1737–1753.
  • Xu B, Jiang M, Chu Y, et al. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2018;68:773–782.
  • Haneklaus M, O’Neill LAJ NLRP3 at the interface of metabolism and inflammation. Immunol Rev. 2015. p. 53–62.
  • Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.
  • van der Meijden PEJ, Heemskerk JWM Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol. 2019;16:166–179.
  • Olsson AK, Cedervall J The pro-inflammatory role of platelets in cancer. Platelets. 2018;29:569–573.
  • Kirschbaum M, Jenne CN, Veldhuis ZJ, et al. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice. Liver Int. 2017;37:1731–1737.
  • Nakano Y, Kondo T, Matsuo R, et al. Platelet dynamics in the early phase of postischemic liver in vivo. J Surg Res 2008;149:192–198.
  • Takahashi K, Murata S, Ohkohchi N Novel therapy for liver regeneration by increasing the number of platelets. Surg. Today. 2013;43:1081–1087.
  • Lalor PF, Herbert J, Bicknell R, et al. Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol. cited 2012 Dec 22. 2013;304:G469–78.
  • Malehmir M, Pfister D, Gallage S, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 2019;25:641–655.
  • Aryal B, Yamakuchi M, Shimizu T, et al. Therapeutic implication of platelets in liver regeneration -hopes and hues. Expert Rev Gastroenterol Hepatol. 2018;12:1219–1228.
  • Chauhan A, Adams DH, Watson SP, et al. Platelets: no longer bystanders in liver disease. Hepatology. 2016;64:1774–1784.
  • Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science. 2006;312:104–107.
  • Ozhan H, Aydin M, Yazici M, et al. Mean platelet volume in patients with non-alcoholic fatty liver disease. Platelets. . 2010;21:29–32.
  • Fujita K, Nozaki Y, Wada K, et al. Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease. Gut. 2008;57:1583–1591.
  • Scull CM, Hays WD, Fischer TH Macrophage pro-inflammatory cytokine secretion is enhanced following interaction with autologous platelets. J Inflamm 2010;7:53.
  • Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549–564.
  • Baron SH Salicylates as Hypoglycemic Agents. Diabetes Care. 1982;5:64.
  • Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 2001;293:1673–1677.
  • Hundal RS, Petersen KF, Mayerson AB, et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 2002;109:1321–1326.
  • Aboyans V, Ricco JB, Bartelink MLEL, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018. p. 763–816.
  • Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019;41:407–477.
  • Rosen V, Wozney JM, Wang EA, et al. Purification and molecular cloning of a novel group of BMPs and localization of BMP mRNA in developing bone. Connect Tissue Res. 1989;20:313–319.
  • Bier E, De Robertis EM EMBRYO DEVELOPMENT. BMP gradients: A paradigm for morphogen-mediated developmental patterning. Science. 2015;348:aaa5838.
  • Herrera B, Addante A, Sanchez A BMP signalling at the crossroad of liver fibrosis and regeneration. Int J Mol Sci. 2017;19(1):39.
  • Muñoz-Félix JM, González-Núñez M, Martínez-Salgado C, et al. TGF-β/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25years of trials and tribulations? Pharmacol Ther. 2015;156:44–58.
  • Morrell NW, Bloch DB, Ten Dijke P, et al. Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 2015;13:106.
  • Do N, Zhao R, Ray K, et al. BMP4 is a novel paracrine inhibitor of liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2012;303:G1220–7.
  • Breitkopf-Heinlein K, Meyer C, Konig C, et al. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut. 2017;66:939–954.
  • Sugimoto H, Yang C, LeBleu VS, et al. BMP-7 functions as a novel hormone to facilitate liver regeneration. Faseb J. 2007;21:256–264.
  • Choi TY, Khaliq M, Tsurusaki S, et al. Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a. Hepatology. 2017;66:1616–1630.
  • Olsavszky V, Ulbrich F, Singh S, et al. GATA4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells. Gene. 2017;627:491–499.
  • Rowe IA, Galsinh SK, Wilson GK, et al. Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication. Hepatology. 2014;59:375–384.
  • Ribera J, Pauta M, Melgar-Lesmes P, et al. A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury. Am J Physiol Gastrointest Liver Physiol. 2017;313:G492–G504.
  • Desroches-Castan A, Tillet E, Ricard N, et al. Bone morphogenetic protein 9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting against hepatic fibrosis. Hepatology. 2019;70:1392–1408.
  • Wang CY, Xiao X, Bayer A, et al. Ablation of hepatocyte Smad1, Smad5, and Smad8 causes severe tissue iron loading and liver fibrosis in mice. Hepatology. 2019;70:1986–2002.
  • Tacke F Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017;66:1300–1312.
  • Kinoshita K, Iimuro Y, Otogawa K, et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut. 2007;56:706–714.
  • Yang T, Chen SL, Lu XJ, et al. Bone morphogenetic protein 7 suppresses the progression of hepatic fibrosis and regulates the expression of gremlin and transforming growth factor beta1. Mol Med Rep. 2012;6:246–252.
  • Fan J, Shen H, Sun Y, et al. Bone morphogenetic protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells. J Cell Physiol. 2006;207:499–505.
  • Arndt S, Wacker E, Dorn C, et al. Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease. Gut. 2015;64:973–981.
  • Blazquez-Medela AM, Jumabay M, Bostrom KI Beyond the bone: bone morphogenetic protein signaling in adipose tissue. Obes Rev. 2019;20:648–658.
  • Saini S, Duraisamy AJ, Bayen S, et al. Role of BMP7 in appetite regulation, adipogenesis, and energy expenditure. Endocrine. 2015;48:405–409.
  • Oral Abstracts (Abstracts 1–288). Hepatology. 2019;70:1–187.
  • Ameer F, Scandiuzzi L, Hasnain S, et al. De novo lipogenesis in health and disease. Metabolism. 2014. p. 895–902.
  • FDA. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment guidance for industry DRAFT GUIDANCE. FDA Off. Doc. 2018
  • Abeles RD, Mullish BH, Forlano R, et al. Derivation and validation of a cardiovascular risk score for prediction of major acute cardiovascular events in non-alcoholic fatty liver disease; the importance of an elevated mean platelet volume. Aliment Pharmacol Ther. 2019; 49:1077–1085.
  • Palma E, Doornebal EJ, Chokshi S Precision-cut liver slices: a versatile tool to advance liver research. Hepatol Int. 2019. 13:51–57.
  • Feaver RE, Cole BK, Lawson MJ, et al. Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight. 2016;1:e90954.
  • Ouchi R, Togo S, Kimura M, et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab. 2019;30:374–384.e6.
  • Skubic C, Ž D, Rozman D Personalized therapy when tackling nonalcoholic fatty liver disease: a focus on sex, genes, and drugs. Expert Opin Drug Metab Toxicol. 2018.14:831–841.
  • Lawitz EJ, Coste A, Poordad F, et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2018;16:1983–1991.e3.

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