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REVIEW

Therapeutic Approaches for Nonalcoholic Fatty Liver Disease: Established Targets and Drugs

, ORCID Icon, ORCID Icon, ORCID Icon, &
Pages 1809-1819 | Received 06 Mar 2023, Accepted 16 Jun 2023, Published online: 21 Jun 2023

References

  • Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431
  • European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402. doi:10.1016/j.jhep.2015.11.004
  • Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis: a review. JAMA. 2020;323(12):1175–1183. doi:10.1001/jama.2020.2298
  • 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(1):11–20. doi:10.1038/nrgastro.2017.109
  • Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology. 2005;42(1):5–13. doi:10.1002/hep.20750
  • Wong VWS, Wong GLH, Chan RSM, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol. 2018;69(6):1349–1356. doi:10.1016/j.jhep.2018.08.011
  • Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048. doi:10.1016/j.metabol.2015.12.012
  • Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–1846. doi:10.1002/hep.24001
  • Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–922. doi:10.1038/s41591-018-0104-9
  • Ghorpade DS, Ozcan L, Zheng Z, et al. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature. 2018;555(7698):673–677. doi:10.1038/nature26138
  • Takeuchi M. Toxic AGEs (TAGE) theory: a new concept for preventing the development of diseases related to lifestyle. Diabetol Metab Syndr. 2020;12(1):105. doi:10.1186/s13098-020-00614-3
  • Adinolfi LE, Petta S, Fracanzani AL, et al. Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: a prospective study. Diabetes Obes Metab. 2020;22(12):2408–2416. doi:10.1111/dom.14168
  • Adinolfi LE, Petta S, Fracanzani AL, et al. Impact of hepatitis C virus clearance by direct-acting antiviral treatment on the incidence of major cardiovascular events: a prospective multicentre study. Atherosclerosis. 2020;296:40–47. doi:10.1016/j.atherosclerosis.2020.01.010
  • Sasso FC, Pafundi PC, Caturano A, et al. Impact of direct acting antivirals (DAAs) on cardiovascular events in HCV cohort with pre-diabetes. Nutr Metab Cardiovasc Dis. 2021;31(8):2345–2353. doi:10.1016/j.numecd.2021.04.016
  • Rinaldi L, Pafundi PC, Galiero R, et al. Mechanisms of non-alcoholic fatty liver disease in the metabolic syndrome. A narrative review. Antioxidants. 2021;10(2):270. doi:10.3390/antiox10020270
  • Masarone M, Rosato V, Aglitti A, et al. Liver biopsy in type 2 diabetes mellitus: steatohepatitis represents the sole feature of liver damage. PLoS One. 2017;12(6):e0178473. doi:10.1371/journal.pone.0178473
  • Jorgačević B, Mladenović D, Ninković M, et al. Rimonabant improves oxidative/nitrosative stress in mice with nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2015;2015:842108. doi:10.1155/2015/842108
  • Gornicka A, Morris-Stiff G, Thapaliya S, Papouchado BG, Berk M, Feldstein AE. Transcriptional profile of genes involved in oxidative stress and antioxidant defense in a dietary murine model of steatohepatitis. Antioxid Redox Signal. 2011;15(2):437–445. doi:10.1089/ars.2010.3815
  • Alswat KA. The role of endocannabinoids system in fatty liver disease and therapeutic potentials. Saudi J Gastroenterol. 2013;19(4):144–151. doi:10.4103/1319-3767.114505
  • Bartelt A, Orlando P, Mele C, et al. Altered endocannabinoid signalling after a high-fat diet in Apoe(-/-) mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance. Diabetologia. 2011;54(11):2900–2910. doi:10.1007/s00125-011-2274-6
  • Park HS, Song JW, Park JH, et al. TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation. Autophagy. 2021;17(9):2549–2564. doi:10.1080/15548627.2020.1834711
  • Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol. 2021;18(3):167–180. doi:10.1038/s41575-020-00376-3
  • Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol. 2021;75(Suppl 1):S67–S81. doi:10.1016/j.jhep.2020.11.013
  • Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–1772. doi:10.2337/db06-1491
  • Honda M, Surewaard BGJ, Watanabe M, et al. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome. Nat Commun. 2020;11(1):1329. doi:10.1038/s41467-020-15068-4
  • De Schepper S, Verheijden S, Aguilera-Lizarraga J, et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell. 2018;175(2):400–415.e13. doi:10.1016/j.cell.2018.07.048
  • Parséus A, Sommer N, Sommer F, et al. Microbiota-induced obesity requires farnesoid X receptor. Gut. 2017;66(3):429–437. doi:10.1136/gutjnl-2015-310283
  • Pierantonelli I, Svegliati-Baroni G. Nonalcoholic fatty liver disease: basic pathogenetic mechanisms in the progression from NAFLD to NASH. Transplantation. 2019;103(1):e1–e13. doi:10.1097/TP.0000000000002480
  • Dong J, Viswanathan S, Adami E, et al. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nat Commun. 2021;12(1):66. doi:10.1038/s41467-020-20303-z
  • Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun. 2020;4(4):478–492. doi:10.1002/hep4.1479
  • Simões ICM, Fontes A, Pinton P, Zischka H, Wieckowski MR. Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol. 2018;95:93–99. doi:10.1016/j.biocel.2017.12.019
  • Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1049–1061. doi:10.1016/j.metabol.2016.02.014
  • Zarei M, Pizarro-Delgado J, Barroso E, Palomer X, Vázquez-Carrera M. Targeting FGF21 for the treatment of nonalcoholic steatohepatitis. Trends Pharmacol Sci. 2020;41(3):199–208. doi:10.1016/j.tips.2019.12.005
  • Kharitonenkov A, DiMarchi R. Fibroblast growth factor 21 night watch: advances and uncertainties in the field. J Intern Med. 2017;281(3):233–246. doi:10.1111/joim.12580
  • Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab. 2015;26(3):153–161. doi:10.1016/j.tem.2015.01.002
  • Hui X, Feng T, Liu Q, Gao Y, Xu A. The FGF21-adiponectin axis in controlling energy and vascular homeostasis. J Mol Cell Biol. 2016;8(2):110–119. doi:10.1093/jmcb/mjw013
  • Dushay J, Lai M. Is trimming the fat enough? Fibroblast growth factor 21 as an emerging treatment for nonalcoholic fatty liver disease. Hepatology. 2019;70(5):1860–1862. doi:10.1002/hep.30789
  • Alvarez-Sola G, Uriarte I, Latasa MU, et al. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017;66(10):1818–1828. doi:10.1136/gutjnl-2016-312975
  • Cicione C, Degirolamo C, Moschetta A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology. 2012;56(6):2404–2411. doi:10.1002/hep.25929
  • Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem. 2009;284(15):10023–10033. doi:10.1074/jbc.M808818200
  • Sciarrillo CM, Keirns BH, Koemel NA, Anderson KL, Emerson SR. Fibroblast growth factor 19: potential modulation of hepatic metabolism for the treatment of non-alcoholic fatty liver disease. Liver Int. 2021;41(5):894–904. doi:10.1111/liv.14802
  • Bougarne N, Weyers B, Desmet SJ, et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr Rev. 2018;39(5):760–802. doi:10.1210/er.2018-00064
  • Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S. Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiol Genomics. 2010;41(1):42–52. doi:10.1152/physiolgenomics.00127.2009
  • Zardi EM, Navarini L, Sambataro G, et al. Hepatic PPARs: their role in liver physiology, fibrosis and treatment. Curr Med Chem. 2013;20(27):3370–3396. doi:10.2174/09298673113209990136
  • Brown E, Hydes T, Hamid A, Cuthbertson DJ. Emerging and established therapeutic approaches for nonalcoholic fatty liver disease. Clin Ther. 2021;43(9):1476–1504. doi:10.1016/j.clinthera.2021.07.013
  • Spence JD, Viscoli CM, Inzucchi SE, et al. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 2019;76(5):526–535. doi:10.1001/jamaneurol.2019.0079
  • DeFronzo RA, Inzucchi S, Abdul-Ghani M, Nissen SE. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res. 2019;16(2):133–143. doi:10.1177/1479164118825376
  • Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–1331. doi:10.1056/NEJMoa1506930
  • Francque S, Szabo G, Abdelmalek MF, et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol. 2021;18(1):24–39. doi:10.1038/s41575-020-00366-5
  • Gupta NA, Mells J, Dunham RM, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51(5):1584–1592. doi:10.1002/hep.23569
  • Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–1705. doi:10.1016/S0140-6736(06)69705-5
  • Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15–30. doi:10.1016/j.cmet.2016.06.009
  • Seino Y, Yabe D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: incretin actions beyond the pancreas. J Diabetes Investig. 2013;4(2):108–130. doi:10.1111/jdi.12065
  • 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(10019):679–690. doi:10.1016/S0140-6736(15)00803-X
  • Fadini GP, Frison V, Rigato M, et al. Trend 2010–2018 in the clinical use of GLP-1 receptor agonists for the treatment of type 2 diabetes in routine clinical practice: an observational study from Northeast Italy. Acta Diabetol. 2020;57(3):367–375. doi:10.1007/s00592-019-01445-z
  • Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011;31(9):1285–1297. doi:10.1111/j.1478-3231.2011.02462.x
  • Eguchi Y, Kitajima Y, Hyogo H, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. 2015;45(3):269–278. doi:10.1111/hepr.12351
  • Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity. 2011;19(12):2310–2315. doi:10.1038/oby.2011.152
  • Teshome G, Ambachew S, Fasil A, Abebe M. Efficacy of glucagon-like peptide-1 analogs in nonalcoholic fatty liver disease: a systematic review. Hepat Med. 2020;12:139–151. doi:10.2147/HMER.S265631
  • Tripathi A, Debelius J, Brenner DA, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15(7):397–411. doi:10.1038/s41575-018-0011-z
  • Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–876. doi:10.3390/nu3100858
  • Takai A, Kikuchi K, Ichimura M, et al. Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis. BMC Gastroenterol. 2020;20(1):46. doi:10.1186/s12876-020-01194-2
  • Chiang JYL. Bile acid metabolism and signaling. Compr Physiol. 2013;3(3):1191–1212. doi:10.1002/cphy.c120023
  • Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15(2):111–128. doi:10.1038/nrgastro.2017.119
  • Hirasawa A, Tsumaya K, Awaji T, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11(1):90–94. doi:10.1038/nm1168
  • Larraufie P, Martin-Gallausiaux C, Lapaque N, et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci Rep. 2018;8(1):74. doi:10.1038/s41598-017-18259-0
  • Sala-Rabanal M, Hirayama BA, Ghezzi C, et al. Revisiting the physiological roles of SGLTs and GLUTs using positron emission tomography in mice. J Physiol. 2016;594(15):4425–4438. doi:10.1113/JP271904
  • Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, et al. Empagliflozin attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) mice by activating autophagy and reducing ER stress and apoptosis. Int J Mol Sci. 2021;22(2):818. doi:10.3390/ijms22020818
  • Inoue M, Hayashi A, Taguchi T, et al. Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease. J Diabetes Investig. 2019;10(4):1004–1011. doi:10.1111/jdi.12980
  • Katsuno K, Fujimori Y, Takemura Y, et al. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J Pharmacol Exp Ther. 2007;320(1):323–330. doi:10.1124/jpet.106.110296
  • Zinman B, Inzucchi SE, Lachin JM, et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48(5):1218–1225. doi:10.1161/STROKEAHA.116.015756
  • Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657. doi:10.1056/NEJMoa1611925
  • Ismail-Beigi F, Moghissi E, Kosiborod M, Inzucchi SE. Shifting paradigms in the medical management of type 2 diabetes: reflections on recent cardiovascular outcome trials. J Gen Intern Med. 2017;32(9):1044–1051. doi:10.1007/s11606-017-4061-7
  • Yokono M, Takasu T, Hayashizaki Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol. 2014;727:66–74. doi:10.1016/j.ejphar.2014.01.040
  • Pradhan R, Yin H, Yu O, Azoulay L. Glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors and risk of nonalcoholic fatty liver disease among patients with type 2 diabetes. Diabetes Care. 2022;45(4):819–829. doi:10.2337/dc21-1953
  • Ding C, Tang Y, Zhu W, et al. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: a network meta-analysis. Acta Diabetol. 2022;59(4):519–533. doi:10.1007/s00592-021-01830-7
  • Raj H, Durgia H, Palui R, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review. World J Diabetes. 2019;10(2):114–132. doi:10.4239/wjd.v10.i2.114
  • Yan H, Huang C, Shen X, Li J, Zhou S, Li W. GLP-1 RAs and SGLT-2 inhibitors for insulin resistance in nonalcoholic fatty liver disease: systematic review and network meta-analysis. Front Endocrinol. 2022;13:923606. doi:10.3389/fendo.2022.923606
  • Chiang JYL. Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 2017;1(1):3–9. doi:10.1016/j.livres.2017.05.001
  • Li T, Chiang JYL, Ma Q. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 2014;66(4):948–983. doi:10.1124/pr.113.008201
  • Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103(10):3920–3925. doi:10.1073/pnas.0509592103
  • Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–582.e1. doi:10.1053/j.gastro.2013.05.042
  • 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(9972):956–965. doi:10.1016/S0140-6736(14)61933-4
  • Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146(3):726–735. doi:10.1053/j.gastro.2013.11.049
  • Mitsuyoshi H, Yasui K, Harano Y, et al. Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol Res. 2009;39(4):366–373. doi:10.1111/j.1872-034X.2008.00464.x
  • 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. Gastroenterology. 2021;161(5):1475–1486. doi:10.1053/j.gastro.2021.07.025
  • Chalasani N, Younossi Z, Lavine JE, et al. 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. Hepatology. 2012;55(6):2005–2023. doi:10.1002/hep.25762
  • Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int. 2017;37(Suppl 1):97–103. doi:10.1111/liv.13302
  • Sarkhy AA, Al-Hussaini AA, Nobili V. Does vitamin E improve the outcomes of pediatric nonalcoholic fatty liver disease? A systematic review and meta-analysis. Saudi J Gastroenterol. 2014;20(3):143–153. doi:10.4103/1319-3767.132983
  • Moser MA, Chun OK. Vitamin C and heart health: a review based on findings from epidemiologic studies. Int J Mol Sci. 2016;17(8):1328. doi:10.3390/ijms17081328
  • Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621–2637. doi:10.1172/JCI31021
  • Rose FJ, Webster J, Barry JB, Phillips LK, Richards AA, Whitehead JP. Synergistic effects of ascorbic acid and thiazolidinedione on secretion of high molecular weight adiponectin from human adipocytes. Diabetes Obes Metab. 2010;12(12):1084–1089. doi:10.1111/j.1463-1326.2010.01297.x