Research advances in pharmacotherapy for nonalcoholic fatty liver disease

Rui JIN; Xiaoxiao WANG; Feng LIU; Huiying RAO

doi:10.3969/j.issn.1001-5256.2022.07.033

Volume 38 Issue 7

Jul. 2022

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Article Navigation > Journal of Clinical Hepatology > 2022 > 38(7): 1634-1640

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Research advances in pharmacotherapy for nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2022.07.033

Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University Hepatology Institute, Peking University People's Hospital, Beijing 100044, China

Research funding:

National Nature Science Foundation of China (81870406)

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Corresponding author: RAO Huiying, rao.huiying@163.com (ORCID: 0000-0003-2431-3872)
Received Date: 2021-11-22
Accepted Date: 2022-01-06
Published Date: 2022-07-20

Abstract

Abstract

The incidence rate of nonalcoholic fatty liver disease (NAFLD) is increasing year by year, and it gradually becomes the most common chronic liver disease in adults and children around the world. Nonalcoholic steatohepatitis (NASH) in its disease spectrum can lead to liver cirrhosis and hepatocellular carcinoma. However, due to the complex pathogenesis of NAFLD, there are currently no effective drugs for treatment. Therefore, the research and development of new drugs for NASH have been a research hotspot in recent years. This article summarizes the pathogenesis of NASH and elaborates on the research advances in potential therapeutic targets and drugs for NASH.
- Non-alcoholic Fatty Liver Disease,
- Nonalcoholic Steatohepatitis,
- Drug Therapy,
- Clinical Trial

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References(46)

References

[1]	HUANG DQ, EL-SERAG HB, LOOMBA R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(4): 223-238. DOI: 10.1038/s41575-020-00381-6.
[2]	Recommendations of the Polish Group of Experts for Non-Alcoholic Fatty Liver Disease (PGE-NAFLD), TOMASIEWICZ K, FLISIAK R, et al. Recommendations for the management of non-alcoholic fatty liver disease (NAFLD)[J]. Clin Exp Hepatol, 2018, 4(3): 153-157. DOI: 10.5114/ceh.2018.78118.
[3]	BERARDO C, di PASQUA LG, CAGNA M, et al. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis: current issues and future perspectives in preclinical and clinical research[J]. Int J Mol Sci, 2020, 21(24). DOI: 10.3390/ijms21249646.
[4]	PAN M, CEDERBAUM AI, ZHANG YL, et al. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production[J]. J Clin Invest, 2004, 113(9): 1277-1287. DOI: 10.1172/JCI19197.
[5]	BUZZETTI E, PINZANI M, TSOCHATZIS EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)[J]. Metabolism, 2016, 65(8): 1038-1048. DOI: 10.1016/j.metabol.2015.12.012.
[6]	HEBBARD L, GEORGE J. Animal models of nonalcoholic fatty liver disease[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(1): 35-44. DOI: 10.1038/nrgastro.2010.191.
[7]	CAI J, ZHANG XJ, LI H. Progress and challenges in the prevention and control of nonalcoholic fatty liver disease[J]. Med Res Rev, 2019, 39(1): 328-348. DOI: 10.1002/med.21515.
[8]	POWELL EE, WONG VW, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397(10290): 2212-2224. DOI: 10.1016/S0140-6736(20)32511-3.
[9]	SUMIDA Y, OKANOUE T, NAKAJIMA A, et al. Phase 3 drug pipelines in the treatment of non-alcoholic steatohepatitis[J]. Hepatol Res, 2019, 49(11): 1256-1262. DOI: 10.1111/hepr.13425.
[10]	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[J]. Lancet, 2019, 394(10215): 2184-2196. DOI: 10.1016/S0140-6736(19)33041-7.
[11]	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[J]. Liver Int, 2019, 39(11): 2082-2093. DOI: 10.1111/liv.14209.
[12]	SUMIDA Y, YONEDA M, OGAWA Y, et al. Current and new pharmacotherapy options for non-alcoholic steatohepatitis[J]. Expert Opin Pharmacother, 2020, 21(8): 953-967. DOI: 10.1080/14656566.2020.1744564.
[13]	FIORUCCI S, BIAGIOLI M, SEPE V, et al. Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)[J]. Expert Opin Investig Drugs, 2020, 29(6): 623-632. DOI: 10.1080/13543784.2020.1763302.
[14]	HARRISON SA, ROSSI SJ, PAREDES AH, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis[J]. Hepatology, 2020, 71(4): 1198-1212. DOI: 10.1002/hep.30590.
[15]	FRANCQUE S, SZABO G, ABDELMALEK MF, et al. Nonalcoholic steatohepatitis: The role of peroxisome proliferator-activated receptors[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 24-39. DOI: 10.1038/s41575-020-00366-5.
[16]	GAWRIEH S, NOUREDDIN M, LOO N, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: A randomized controlled double-blind phase 2 trial[J]. Hepatology, 2021, 74(4): 1809-1824. DOI: 10.1002/hep.31843.
[17]	STAELS B, RUBENSTRUNK A, NOEL B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Hepatology, 2013, 58(6): 1941-1952. DOI: 10.1002/hep.26461.
[18]	HARRISON S, RATZIU V, ANSTEE QM, et al. Baseline levels of NIS4TM and other fibrosis biomarkers and prediction of histological progression to advanced fibrosis in NASH[J]. Hepatology 72(S1): 896A.
[19]	LEFERE S, PUENGEL T, HUNDERTMARK J, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages[J]. J Hepatol, 2020, 73(4): 757-770. DOI: 10.1016/j.jhep.2020.04.025.
[20]	VATNER DF, WEISMANN D, BEDDOW SA, et al. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways[J]. Am J Physiol Endocrinol Metab, 2013, 305(1): E89- E100. DOI: 10.1152/ajpendo.00573.2012.
[21]	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[J]. Lancet, 2019, 394(10213): 2012-2024. DOI: 10.1016/S0140-6736(19)32517-6.
[22]	KHARITONENKOV A, ADAMS AC. Inventing new medicines: The FGF21 story[J]. Mol Metab, 2014, 3(3): 221-229. DOI: 10.1016/j.molmet.2013.12.003.
[23]	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[J]. Lancet, 2019, 392(10165): 2705-2717. DOI: 10.1016/S0140-6736(18)31785-9.
[24]	HARRISON SA, RUANE PJ, FREILICH BL, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial[J]. Nat Med, 2021, 27(7): 1262-1271. DOI: 10.1038/s41591-021-01425-3.
[25]	DOBRZYN P, DOBRZYN A, MIYAZAKI M, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver[J]. Proc Natl Acad Sci U S A, 2004, 101(17): 6409-6414. DOI: 10.1073/pnas.0401627101.
[26]	LOOMBA R, MOHSENI R, LUCAS KJ, et al. TVB-2640 (FASN Inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial[J]. Gastroenterology, 2021, 161(5): 1475-1486. DOI: 10.1053/j.gastro.2021.07.025.
[27]	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[J]. Cell Metab, 2017, 26(3): 576. DOI: 10.1016/j.cmet.2017.08.011.
[28]	CALLE RA, AMIN NB, CARVAJAL-GONZALEZ S, et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: Two parallel, placebo-controlled, randomized phase 2a trials[J]. Nat Med, 2021, 27(10): 1836-1848. DOI: 10.1038/s41591-021-01489-1.
[29]	LOOMBA R, MORGAN E, WATTS L, et al. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial[J]. Lancet Gastroenterol Hepatol, 2020, 5(9): 829-838. DOI: 10.1016/S2468-1253(20)30186-2.
[30]	CUSI K, ALKHOURI N, HARRISON SA, et al. Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study[J]. Lancet Gastroenterol Hepatol, 2021, 6(11): 889-902. DOI: 10.1016/S2468-1253(21)00300-9.
[31]	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[J]. Lancet, 2016, 387(10019): 679-690. DOI: 10.1016/S0140-6736(15)00803-X.
[32]	HARTMAN ML, SANYAL AJ, LOOMBA R, et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes[J]. Diabetes Care, 2020, 43(6): 1352-1355. DOI: 10.2337/dc19-1892.
[33]	CUI J, PHILO L, NGUYEN P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial[J]. J Hepatol, 2016, 65(2): 369-376. DOI: 10.1016/j.jhep.2016.04.021.
[34]	COLCA JR, MCDONALD WG, ADAMS WJ. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis[J]. Expert Opin Investig Drugs, 2018, 27(7): 631-636. DOI: 10.1080/13543784.2018.1494153.
[35]	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]. J Hepatol, 2020, 72(4): 613-626. DOI: 10.1016/j.jhep.2019.10.023.
[36]	SAFADI R, BRAUN M, FRANCIS A, et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis[J]. Aliment Pharmacol Ther, 2021, 54(11-12): 1405-1415. DOI: 10.1111/apt.16664.
[37]	FRIEDMAN SL, RATZIU V, HARRISON SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis[J]. Hepatology, 2018, 67(5): 1754-1767. DOI: 10.1002/hep.29477.
[38]	RATZIU V, SANYAL A, HARRISON SA, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study[J]. Hepatology, 2020, 72(3): 892-905. DOI: 10.1002/hep.31108.
[39]	ANSTEE QM, NEUSCHWANDER-TETRI BA, WONG VW, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design[J]. Contemp Clin Trials, 2020, 89: 105922. DOI: 10.1016/j.cct.2019.105922.
[40]	BRENNER C, GALLUZZI L, KEPP O, et al. Decoding cell death signals in liver inflammation[J]. J Hepatol, 2013, 59(3): 583-594. DOI: 10.1016/j.jhep.2013.03.033.
[41]	HSU MC, LIU SH, WANG CW, et al. JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis[J]. Eur J Pharmacol, 2017, 812: 113-120. DOI: 10.1016/j.ejphar.2017.07.012.
[42]	HENDERSON NC, SETHI T. The regulation of inflammation by galectin-3[J]. Immunol Rev, 2009, 230(1): 160-171. DOI: 10.1111/j.1600-065X.2009.00794.x.
[43]	HARRISON SA, MARRI SR, CHALASANI N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis[J]. Aliment Pharmacol Ther, 2016, 44(11-12): 1183-1198. DOI: 10.1111/apt.13816.
[44]	CHALASANI N, ABDELMALEK MF, GARCIA-TSAO G, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension[J]. Gastroenterology, 2020, 158(5): 1334-1345. e5. DOI: 10.1053/j.gastro.2019.11.296.
[45]	HARRISON SA, ABDELMALEK MF, CALDWELL S, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis[J]. Gastroenterology, 2018, 155(4): 1140-1153. DOI: 10.1053/j.gastro.2018.07.006.
[46]	MCPHERSON S, WILKINSON N, TINIAKOS D, et al. A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis[J]. PLoS One, 2017, 12(4): e0175717. DOI: 10.1371/journal.pone.0175717.

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Research advances in pharmacotherapy for nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2022.07.033

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Research advances in pharmacotherapy for nonalcoholic fatty liver disease

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