Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates
Abstract
:1. Introduction
2. THRβ Agonists
3. Lipogenesis Inhibitors
3.1. ACC Inhibitors
3.2. FASN Inhibitors
3.3. SCD1 Inhibitors
3.4. DGAT Inhibitors
3.5. ω-3 PUFAs
4. Bile Acid Metabolism Modulators
4.1. FXR Agonists
4.2. FGF Analogues
5. Fibrogenesis Inhibitors
5.1. Galectin Antagonists
5.2. TLR4 Antagonists
5.3. LOXL2 Inhibitors
5.4. ATX Inhibitors
6. Glucose Metabolism Modulators
6.1. PPAR Agonists
6.2. MPC Inhibitors
6.3. Incretin Mimetics
6.4. SGLT Inhibitors
6.5. α-Glucosidase Inhibitors
7. Other Agents
7.1. Probiotics
7.2. Mesenchymal Stromal Cells
7.3. Fraudulent Fatty Acids
7.4. Tesamorelin
7.5. Berberine Ursodeoxycholate
7.6. Miricorilant
7.7. Nitazoxanide
7.8. Pirfenidone
7.9. Miscellaneous
8. Future Directions
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- 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, 1388–1402. [Google Scholar] [CrossRef] [PubMed]
- Monelli, F.; Venturelli, F.; Bonilauri, L.; Manicardi, E.; Manicardi, V.; Giorgi Rossi, P.; Massari, M.; Ligabue, G.; Riva, N.; Schianchi, S.; et al. Systematic review of existing guidelines for NAFLD assessment. Hepatoma Res. 2021, 7, 25. [Google Scholar] [CrossRef]
- Estes, C.; Razavi, H.; Loomba, R.; Younossi, Z.; Sanyal, A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018, 67, 123–133. [Google Scholar] [CrossRef] [PubMed]
- Eslam, M.; Sanyal, A.J.; George, J.; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020, 158, 1999–2014.e1. [Google Scholar] [CrossRef]
- Attia, S.L.; Softic, S.; Mouzaki, M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin. Transl. Sci. 2021, 14, 11–19. [Google Scholar] [CrossRef] [PubMed]
- Yoneda, M.; Honda, Y.; Saito, S.; Nakajima, A. What considerations are there for the pharmacotherapeutic management of nonalcoholic steatohepatitis? Expert Opin. Pharmacother. 2021, 22, 1217–1220. [Google Scholar] [CrossRef]
- Ortiga-Carvalho, T.M.; Sidhaye, A.R.; Wondisford, F.E. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat. Rev. Endocrinol. 2014, 10, 582–591. [Google Scholar] [CrossRef] [Green Version]
- Pramfalk, C.; Pedrelli, M.; Parini, P. Role of thyroid receptor β in lipid metabolism. Biochim. Biophys. Acta 2011, 1812, 929–937. [Google Scholar] [CrossRef] [Green Version]
- Dawson, P.A.; Parini, P. Hepatic thyroid hormone receptor β1 agonism: Good for lipids, good for bile? J. Lipid Res. 2018, 59, 1551–1553. [Google Scholar] [CrossRef] [Green Version]
- Gionfra, F.; De Vito, P.; Pallottini, V.; Lin, H.Y.; Davis, P.J.; Pedersen, J.Z.; Incerpi, S. The Role of Thyroid Hormones in Hepatocyte Proliferation and Liver Cancer. Front. Endocrinol. 2019, 10, 532. [Google Scholar] [CrossRef] [Green Version]
- Harrison, S.A.; Bashir, M.; Moussa, S.E.; McCarty, K.; Frias, J.P.; Taub, R.; Alkhouri, N. Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients with NASH. Hepatol. Commun. 2021, 5, 573–588. [Google Scholar] [CrossRef] [PubMed]
- Loomba, R.; Neutel, J.; Mohseni, R.; Bernard, D.; Severance, R.; Dao, M.; Saini, S.; Margaritescu, C.; Homer, K.; Tran, B.; et al. VK2809, a Novel Liver-Directed Thyroid Receptor Beta Agonist, Significantly Reduces Liver Fat with Both Low and High Doses in Patients with Non-Alcoholic Fatty Liver Disease: A Phase 2 Randomized, Placebo-Controlled Trial. J. Hepatol. 2019, 70, e141–e382. [Google Scholar] [CrossRef]
- Li, X.; He, H.; Sho, E.; Yang, B.; Wu, J.J. Significant Improvement of NAFLD Activity Scores and Liver Fibrosis by ASC41, a Selective THR-β Agonist, in High Fat Diet Induced NASH SD Rats. In Proceedings of the Digital International Liver Congress 2021, Virtual, 23–26 June 2021. [Google Scholar]
- Wu, J.; He, H.; Palmer, M.; Yan, Y. A Phase Ib Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Asc41, A THR-Β Agonist, for 28-Days in Overweight and Obese Subjects with Elevated LDL-C, a Population Characteristic of NAFLD. In Proceedings of the Liver Meeting 2021, Virtual, 12–15 November 2021. [Google Scholar]
- Kirschberg, T.; Jones, C.; Xu, Y.; Wang, Y.; Fenaux, M.; Klucher, K. TERN-501, a Potent and Selective Agonist of Thyroid Hormone Receptor Beta, Strongly Reduces Histological Features and Biomarkers of Non-Alcoholic Steatohepatitis Associated Pathology in Rodent Models. In Proceedings of the Digital International Liver Congress 2020, Virtual, 27–29 August 2020. [Google Scholar]
- Ascletis Pharma Inc. Available online: https://ascletis.com/ (accessed on 10 December 2021).
- Terns Pharmaceuticals. Available online: https://www.ternspharma.com/ (accessed on 10 December 2021).
- Qi, J.; Lang, W.; Geisler, J.G.; Wang, P.; Petrounia, I.; Mai, S.; Smith, C.; Askari, H.; Struble, G.T.; Williams, R.; et al. The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2. J. Lipid Res. 2012, 53, 1106–1116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.X.; Diehl, A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45, 1366–1374. [Google Scholar] [CrossRef] [PubMed]
- Takemoto, K.; Fukasaka, Y.; Yoshimoto, R.; Nambu, H.; Yukioka, H. Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. Physiol. Rep. 2020, 8, e14542. [Google Scholar] [CrossRef]
- Parlati, L.; Régnier, M.; Guillou, H.; Postic, C. New targets for NAFLD. JHEP Rep. 2021, 3, 100346. [Google Scholar] [CrossRef]
- Panzitt, K.; Wagner, M. FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochim. Biophys. Acta Mol. Basis Dis. 2021, 1867, 166133. [Google Scholar] [CrossRef]
- Loomba, R.; Noureddin, M.; Kowdley, K.V.; Kohli, A.; Sheikh, A.; Neff, G.; Bhandari, B.R.; Gunn, N.; Caldwell, S.H.; Goodman, Z.; et al. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology 2021, 73, 625–643. [Google Scholar] [CrossRef]
- Calle, R.A.; Amin, N.B.; Carvajal-Gonzalez, S.; Ross, T.T.; Bergman, A.; Aggarwal, S.; Crowley, C.; Rinaldi, A.; Mancuso, J.; Aggarwal, N.; 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. Nat. Med. 2021, 27, 1836–1848. [Google Scholar] [CrossRef]
- Syed-Abdul, M.M.; Parks, E.J.; Gaballah, A.H.; Bingham, K.; Hammoud, G.M.; Kemble, G.; Buckley, D.; McCulloch, W.; Manrique-Acevedo, C. Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males with Metabolic Abnormalities. Hepatology 2020, 72, 103–118. [Google Scholar] [CrossRef]
- Loomba, R.; Rinella, M.; Harrison, S.A.; Wong, V.W.-S.; Ratziu, V.; Mohseni, R.; Lucas, J.; Gutierrez, J.A.; Rahimi, R.; Trotter, J.; et al. Novel, first-in-class, fatty acid synthase inhibitor, TVB-2640 versus placebo demonstrates clinically significant reduction in liver fat by MRI-PDFF in NASH. In Proceedings of the Digital International Liver Congress 2020, Virtual, 27–29 August 2020. [Google Scholar]
- Forma Therapeutics. Available online: https://www.formatherapeutics.com/ (accessed on 10 December 2021).
- Bhattacharya, D.; Basta, B.; Mato, J.M.; Craig, A.; Fernández-Ramos, D.; Lopitz-Otsoa, F.; Tsvirkun, D.; Hayardeny, L.; Chandar, V.; Schwartz, R.E.; et al. Aramchol downregulates stearoyl CoA-desaturase 1 in hepatic stellate cells to attenuate cellular fibrogenesis. JHEP Rep. 2021, 3, 100237. [Google Scholar] [CrossRef] [PubMed]
- Leikin-Frenkel, A.; Gonen, A.; Shaish, A.; Goldiner, I.; Leikin-Gobbi, D.; Konikoff, F.M.; Harats, D.; Gilat, T. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A desaturase and is non-atherogenic. Arch. Med. Res. 2010, 41, 397–404. [Google Scholar] [CrossRef] [PubMed]
- Ratziu, V.; de Guevara, L.; Safadi, R.; Poordad, F.; Fuster, F.; Flores-Figueroa, J.; Arrese, M.; Fracanzani, A.L.; Ben Bashat, D.; Lackner, K.; et al. Aramchol in patients with nonalcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase 2b trial. Nat. Med. 2021, 27, 1825–1835. [Google Scholar] [CrossRef] [PubMed]
- Calle, R.; Aggarwal, S.; Mancuso, J.; Bergman, A.; Somayaji, V.; Ross, T.; Esler, W. Co-administration of PF-05221304 and PF-06865571 delivers robust whole liver fat reduction and mitigation of acetyl-coa carboxilase inhibitor induced hypertriglyceridemia in patients with NAFLD. J. Hepatol. 2020, 73, S401–S652. [Google Scholar] [CrossRef]
- Loomba, R.; Morgan, E.; Watts, L.; Xia, S.; Hannan, L.A.; Geary, R.S.; Baker, B.F.; Bhanot, S. 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. Lancet Gastroenterol. Hepatol. 2020, 5, 829–838. [Google Scholar] [CrossRef]
- Sinew Pharma Inc. Available online: https://www.sinewpharma.com/en/ (accessed on 10 December 2021).
- Dentin, R.; Benhamed, F.; Pégorier, J.P.; Foufelle, F.; Viollet, B.; Vaulont, S.; Girard, J.; Postic, C. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J. Clin. Investig. 2005, 115, 2843–2854. [Google Scholar] [CrossRef] [Green Version]
- Calder, P.C. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr. 2006, 83, 1505S–1519S. [Google Scholar] [CrossRef]
- Siriwardhana, N.; Kalupahana, N.S.; Moustaid-Moussa, N. Health benefits of n-3 polyunsaturated fatty acids: Eicosapentaenoic acid and docosahexaenoic acid. Adv. Food Nutr. Res. 2012, 65, 211–222. [Google Scholar] [CrossRef]
- Okada, L.S.D.R.R.; Oliveira, C.P.; Stefano, J.T.; Nogueira, M.A.; Silva, I.D.C.G.D.; Cordeiro, F.B.; Alves, V.A.F.; Torrinhas, R.S.; Carrilho, F.J.; Puri, P.; et al. Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH-Proteomic and lipidomic insight. Clin. Nutr. 2018, 37, 1474–1484. [Google Scholar] [CrossRef]
- Nogueira, M.A.; Oliveira, C.P.; Ferreira Alves, V.A.; Stefano, J.T.; Rodrigues, L.S.; Torrinhas, R.S.; Cogliati, B.; Barbeiro, H.; Carrilho, F.J.; Waitzberg, D.L. Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial. Clin. Nutr. 2016, 35, 578–586. [Google Scholar] [CrossRef]
- Parker, H.M.; Johnson, N.A.; Burdon, C.A.; Cohn, J.S.; O’Connor, H.T.; George, J. Omega-3 supplementation and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J. Hepatol. 2012, 56, 944–951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nobili, V.; Bedogni, G.; Alisi, A.; Pietrobattista, A.; Risé, P.; Galli, C.; Agostoni, C. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: Double-blind randomised controlled clinical trial. Arch. Dis. Child. 2011, 96, 350–353. [Google Scholar] [CrossRef] [PubMed]
- He, X.X.; Wu, X.L.; Chen, R.P.; Chen, C.; Liu, X.G.; Wu, B.J.; Huang, Z.M. Effectiveness of Omega-3 Polyunsaturated Fatty Acids in Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. PLoS ONE 2016, 11, e0162368. [Google Scholar] [CrossRef] [PubMed]
- Yan, J.H.; Guan, B.J.; Gao, H.Y.; Peng, X.E. Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials. Medicine 2018, 97, e12271. [Google Scholar] [CrossRef]
- Lee, C.H.; Fu, Y.; Yang, S.J.; Chi, C.C. Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation on Non-Alcoholic Fatty Liver: A Systematic Review and Meta-Analysis. Nutrients 2020, 12, 2769. [Google Scholar] [CrossRef]
- Climax, J.; Newsome, P.N.; Hamza, M.; Weissbach, M.; Coughlan, D.; Sattar, N.; McGuire, D.K.; Bhatt, D.L. Effects of Epeleuton, a Novel Synthetic Second-Generation n-3 Fatty Acid, on Non-Alcoholic Fatty Liver Disease, Triglycerides, Glycemic Control, and Cardiometabolic and Inflammatory Markers. J. Am. Heart Assoc. 2020, 9, e016334. [Google Scholar] [CrossRef]
- Affimune. Available online: https://www.afimmune.com/ (accessed on 10 December 2021).
- Harrison, S.; Gunn, N.T.; Sheikh, M.Y.; Rudraraju, M.; Kohli, A.; Neff, G.; Round, P.; Fraser, D.A.; Beysen, C.; Rossi, S.; et al. Icosabutate, a novel structurally engineered fatty acid, significantly reduces relevant markers of NASH and fibrosis in 16 weeks: Interim analysis results of the ICONA trial. J. Hepatol. 2021, 75, S294–S803. [Google Scholar]
- Jiang, L.; Zhang, H.; Xiao, D.; Wei, H.; Chen, Y. Farnesoid X receptor (FXR): Structures and ligands. Comput. Struct. Biotechnol. J. 2021, 19, 2148–2159. [Google Scholar] [CrossRef]
- Intercept Pharmaceuticals. Available online: https://www.interceptpharma.com/homepage-non-usa/ (accessed on 10 December 2021).
- Mudaliar, S.; Henry, R.R.; Sanyal, A.J.; Morrow, L.; Marschall, H.U.; Kipnes, M.; Adorini, L.; Sciacca, C.I.; Clopton, P.; Castelloe, E.; 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, 574–582.e1. [Google Scholar] [CrossRef]
- Neuschwander-Tetri, B.A.; Loomba, R.; Sanyal, A.J.; Lavine, J.E.; Van Natta, M.L.; Abdelmalek, M.F.; Chalasani, N.; Dasarathy, S.; Diehl, A.M.; Hameed, B.; 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. [Google Scholar] [CrossRef] [Green Version]
- Alemi, F.; Kwon, E.; Poole, D.P.; Lieu, T.; Lyo, V.; Cattaruzza, F.; Cevikbas, F.; Steinhoff, M.; Nassini, R.; Materazzi, S.; et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J. Clin. Investig. 2013, 123, 1513–1530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- An, P.; Wei, G.; Huang, P.; Li, W.; Qi, X.; Lin, Y.; Vaid, K.A.; Wang, J.; Zhang, S.; Li, Y.; et al. A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction. Liver Int. 2020, 40, 1655–1669. [Google Scholar] [CrossRef] [PubMed]
- Chau, M.; Li, Y.; Roqueta-Rivera, M.; Garlick, K.; Shen, R.; Wang, G.; Or, Y.S.; Jiang, L.-J. Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis. Int. J. Gastroenterol. 2019, 3, 4–16. [Google Scholar] [CrossRef]
- Enanta Pharmaceuticals, Inc. Enanta Announces Results of INTREPID Study of EDP-305 for the Treatment of Primary Biliary Cholangitis: News Release; 2020. Available online: https://www.enanta.com/investors/news-releases/press-release/2020/Enanta-Announces-Results-of-INTREPID-Study-of-EDP-305-for-the-Treatment-of-Primary-Biliary-Cholangitis/default.aspx (accessed on 10 December 2021).
- Biagioli, M.; Fiorucci, S. Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease. Liver Res. 2021, 5, 119–141. [Google Scholar] [CrossRef]
- Enanta Pharmaceuticals, Inc. Enanta Pharmaceuticals Provides Update on NASH FXR Agonist Programs: News Release; 2021. Available online: https://www.enanta.com/investors/news-releases/press-release/2021/Enanta-Pharmaceuticals-Provides-Update-on-NASH-FXR-Agonist-Programs/ (accessed on 10 December 2021).
- Carino, A.; Cipriani, S.; Marchianò, S.; Biagioli, M.; Santorelli, C.; Donini, A.; Zampella, A.; Monti, M.C.; Fiorucci, S. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci. Rep. 2017, 7, 42801. [Google Scholar] [CrossRef]
- Roth, J.D.; Feigh, M.; Veidal, S.S.; Fensholdt, L.K.; Rigbolt, K.T.; Hansen, H.H.; Chen, L.C.; Petitjean, M.; Friley, W.; Vrang, N.; et al. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J. Gastroenterol. 2018, 24, 195–210. [Google Scholar] [CrossRef]
- Harrison, S.A.; Bashir, M.R.; Lee, K.J.; Shim-Lopez, J.; Lee, J.; Wagner, B.; Smith, N.D.; Chen, H.C.; Lawitz, E.J. A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis. J. Hepatol. 2021, 75, 25–33. [Google Scholar] [CrossRef]
- Kremoser, C. FXR agonists for NASH: How are they different and what difference do they make? J. Hepatol. 2021, 75, 12–15. [Google Scholar] [CrossRef]
- Schumacher, J.D.; Guo, G.L. Pharmacologic Modulation of Bile Acid-FXR-FGF15/FGF19 Pathway for the Treatment of Nonalcoholic Steatohepatitis. Handb. Exp. Pharmacol. 2019, 256, 325–357. [Google Scholar] [CrossRef]
- Lucas, K.J.; Lopez, P.; Lawitz, E.; Sheikh, A.; Aizenberg, D.; Hsia, S.; Boon Bee, G.G.; Vierling, J.; Frias, J.; White, J.; et al. Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results. Dig. Liver Dis. 2020, 52, e19–e45. [Google Scholar] [CrossRef]
- Novartis. A Randomized, Double-Blind, Placebo Controlled, 3-Part, Adaptive Design, Multicenter Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in Patients with Non-Alcoholic Steatohepatitis (NASH): FLIGHT-FXR, 2020. Available online: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17816 (accessed on 10 December 2021).
- Patel, K.; Harrison, S.A.; Elkhashab, M.; Trotter, J.F.; Herring, R.; Rojter, S.E.; Kayali, Z.; Wong, V.W.; Greenbloom, S.; Jayakumar, S.; et al. Cilofexor, a Nonsteroidal FXR Agonist, in Patients with Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Hepatology 2020, 72, 58–71. [Google Scholar] [CrossRef] [PubMed]
- Harrison, S.A.; Ratziu, V.; White, A.; Reiss, G.M.; Bowman, W.K.; Gunn, N.; Loustaud Ratti, V.; Bureau, C.; Lawitz, E.J.; Alkhouri, N.; et al. Vonafexor, s FXR Agonist, Induced Hepatic snd Renal Improvement in the Randomized, Double-Blind, Placebocontrolled LIVIFYNASH Trial. In Proceedings of the Liver Meeting 2021, Virtual, 12–15 November 2021. [Google Scholar]
- Novartis. A randomized, Patient and Investigator Blinded, Placebo-Controlled, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of LMB763 in Patients with Non-Alcoholic Steatohepatitis (NASH), 2020. Available online: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17527 (accessed on 10 December 2021).
- Loomba, R.; Kowdley, K.V.; Vuppalanchi, R.; Hassanein, T.; Rojter, S.E.; Sheikh, M.Y.; Moussa, S.; Chung, D.; Eng, C.; Marmon, T.; et al. Liver-Distributed FXR Agonist TERN-101 Demonstrates Favorable Safety and Efficacy Profile in NASH Phase 2a LIFT Study. Hepatology 2021, 74, 97A–98A. [Google Scholar]
- Hepagene Therapeutics, Inc. Available online: http://www.hepagene.com/#/m_about2 (accessed on 10 December 2021).
- Henriksson, E.; Andersen, B. FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 from Mice to Human. Front. Endocrinol. 2020, 11, 601349. [Google Scholar] [CrossRef] [PubMed]
- Harrison, S.A.; Abdelmalek, M.F.; Neff, G.W.; Gunn, N.; Guy, C.D.; Alkhouri, N.; Bashir, M.; Freilich, B.; Almeda, J.; Knapple, W.; et al. Topline Results from the ALPINE 2/3 Study: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2b Trial Evaluating 3 Doses of the FGF19 Analogue Aldafermin on Liver Histology in Patients with Nonalcoholic Steatohepatitis and Stage 2 or 3 Fibrosis. Hepatology 2021, 74, 5A. [Google Scholar]
- Harrison, S.A.; Ruane, P.J.; Freilich, B.L.; Neff, G.; Patil, R.; Behling, C.A.; Hu, C.; Fong, E.; de Temple, B.; Tillman, E.J.; et al. Efruxifermin in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled, phase 2a trial. Nat. Med. 2021, 27, 1262–1271. [Google Scholar] [CrossRef]
- Frias, J.P.; Lawitz, E.J.; Ortiz-LaSanta, G.; Franey, B.; Morrow, L.; Chen, C.-Y.; Tseng, L.; Charlton, R.W.; Mansbach, H.; Margalit, M.; et al. BIO89-100 Demonstrated Robust Reductions in Liver Fat and Liver Fat Volume (LFV) by MRI-PDFF, Favorable Tolerability and Potential for Weekly (QW) or Every 2 Weeks (Q2W) Dosing in a Phase 1b/2a Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study in NASH. J. Endocr. Soc. 2021, 5, A5–A6. [Google Scholar] [CrossRef]
- Novo Nordisk. Available online: https://www.novonordisk.com/ (accessed on 10 December 2021).
- Baruch, A.; Wong, C.; Chinn, L.W.; Vaze, A.; Sonoda, J.; Gelzleichter, T.; Chen, S.; Lewin-Koh, N.; Morrow, L.; Dheerendra, S.; et al. Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans. Proc. Natl. Acad. Sci. USA 2020, 117, 28992–29000. [Google Scholar] [CrossRef]
- Pan, Q.; Lin, S.; Li, Y.; Liu, L.; Li, X.; Gao, X.; Yan, J.; Gu, B.; Chen, X.; Li, W.; et al. A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis. EBioMedicine 2021, 63, 103202. [Google Scholar] [CrossRef]
- Abdelmalek, M.F.; Sanyal, A.J.; Nakajima, A.; Neuschwander-Tetri, B.A.; Goodman, Z.; Lawitz, E.J.; Harrison, S.A.; Jacobson, I.M.; Imajo, K.; Gunn, N.; et al. Efficacy and Safety of Pegbelfermin in Patients with Nonalcoholic Steatohepatitis and Compensated Cirrhosis: Results from the Phase 2b, Randomized, Double-Blind, Placebo-Controlled Falcon 2 Study. In Proceedings of the Liver Meeting 2021, Virtual, 12–15 November 2021. [Google Scholar]
- Sun, M.J.; Cao, Z.Q.; Leng, P. The roles of galectins in hepatic diseases. J. Mol. Histol. 2020, 51, 473–484. [Google Scholar] [CrossRef]
- An, Y.; Xu, S.; Liu, Y.; Xu, X.; Philips, C.A.; Chen, J.; Méndez-Sánchez, N.; Guo, X.; Qi, X. Role of Galectins in the Liver Diseases: A Systematic Review and Meta-Analysis. Front. Med. 2021, 8, 744518. [Google Scholar] [CrossRef]
- Traber, P.G.; Chou, H.; Zomer, E.; Hong, F.; Klyosov, A.; Fiel, M.I.; Friedman, S.L. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 2013, 8, e75361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chalasani, N.; Abdelmalek, M.F.; Garcia-Tsao, G.; Vuppalanchi, R.; Alkhouri, N.; Rinella, M.; Noureddin, M.; Pyko, M.; Shiffman, M.; Sanyal, A.; et al. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients with Nonalcoholic Steatohepatitis with Cirrhosis and Portal Hypertension. Gastroenterology 2020, 158, 1334–1345.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hsieh, Y.C.; Lee, K.C.; Wu, P.S.; Huo, T.I.; Huang, Y.H.; Hou, M.C.; Lin, H.C. Eritoran Attenuates Hepatic Inflammation and Fibrosis in Mice with Chronic Liver Injury. Cells 2021, 10, 1562. [Google Scholar] [CrossRef]
- Yang, L.; Seki, E. Toll-like receptors in liver fibrosis: Cellular crosstalk and mechanisms. Front. Physiol. 2012, 3, 138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, K.C.; Chen, M.Y.; Lin, C.L.; Yang, S.S.; Hsu, C.W.; Wang, C.C.; Huang, Y.H.; Chang, C.C.; Shih, Y.C.; Liu, S.H. JKB-111 in Patients with Non-Alcoholic Fatty Liver: A Phase 2 Randomized Double-Blind Placebo-Control Study. In Proceedings of the Digital International Liver Congress 2020, Virtual, 27–29 August 2020. [Google Scholar]
- Klepfish, M.; Gross, T.; Vugman, M.; Afratis, N.A.; Havusha-Laufer, S.; Brazowski, E.; Solomonov, I.; Varol, C.; Sagi, I. LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis. Front. Immunol. 2020, 11, 480. [Google Scholar] [CrossRef]
- Chen, W.; Yang, A.; Jia, J.; Popov, Y.V.; Schuppan, D.; You, H. Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis. Hepatology 2020, 72, 729–741. [Google Scholar] [CrossRef]
- Harrison, S.A.; Abdelmalek, M.F.; Caldwell, S.; Shiffman, M.L.; Diehl, A.M.; Ghalib, R.; Lawitz, E.J.; Rockey, D.C.; Schall, R.A.; Jia, C.; et al. Simtuzumab Is Ineffective for Patients with Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology 2018, 155, 1140–1153. [Google Scholar] [CrossRef]
- Schilter, H.; Findlay, A.D.; Perryman, L.; Yow, T.T.; Moses, J.; Zahoor, A.; Turner, C.I.; Deodhar, M.; Foot, J.S.; Zhou, W.; et al. The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis. J. Cell. Mol. Med. 2019, 23, 1759–1770. [Google Scholar] [CrossRef] [Green Version]
- Galecto, Inc. Available online: https://galecto.com/ (accessed on 10 December 2021).
- Geraldo, L.H.M.; Spohr, T.C.L.S.; Amaral, R.F.D.; Fonseca, A.C.C.D.; Garcia, C.; Mendes, F.A.; Freitas, C.; dos Santos, M.F.; Lima, F.R.S. Role of lysophosphatidic acid and its receptors in health and disease: Novel therapeutic strategies. Signal Transduct. Target. Ther. 2021, 6, 45. [Google Scholar] [CrossRef]
- Bain, G.; Shannon, K.E.; Huang, F.; Darlington, J.; Goulet, L.; Prodanovich, P.; Ma, G.L.; Santini, A.M.; Stein, A.J.; Lonergan, D.; et al. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis. J. Pharmacol. Exp. Ther. 2017, 360, 1–13. [Google Scholar] [CrossRef]
- TaiwanJ Pharmaceuticals. Available online: https://www.taiwanj.com/pages/page_index_en (accessed on 10 December 2021).
- Boeckmans, J.; Natale, A.; Rombaut, M.; Buyl, K.; Rogiers, V.; De Kock, J.; Vanhaecke, T.; Rodrigues, R.M. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019, 9, 37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Athyros, V.G.; Mikhailidis, D.P.; Didangelos, T.P.; Giouleme, O.I.; Liberopoulos, E.N.; Karagiannis, A.; Kakafika, A.I.; Tziomalos, K.; Burroughs, A.K.; Elisaf, M.S. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: A randomised study. Curr. Med. Res. Opin. 2006, 22, 873–883. [Google Scholar] [CrossRef] [PubMed]
- Fernández-Miranda, C.; Pérez-Carreras, M.; Colina, F.; López-Alonso, G.; Vargas, C.; Solís-Herruzo, J.A. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig. Liver Dis. 2008, 40, 200–205. [Google Scholar] [CrossRef] [PubMed]
- Basaranoglu, M.; Acbay, O.; Sonsuz, A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J. Hepatol. 1999, 31, 384. [Google Scholar] [CrossRef]
- Laurin, J.; Lindor, K.D.; Crippin, J.S.; Gossard, A.; Gores, G.J.; Ludwig, J.; Rakela, J.; McGill, D.B. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: A pilot study. Hepatology 1996, 23, 1464–1467. [Google Scholar] [CrossRef]
- Hatanaka, T.; Kosone, T.; Saito, N.; Takakusagi, S.; Tojima, H.; Naganuma, A.; Takagi, H.; Uraoka, T.; Kakizaki, S. Effect of 48-week pemafibrate on non-alcoholic fatty liver disease with hypertriglyceridemia, as evaluated by the FibroScan-aspartate aminotransferase score. JGH Open 2021, 5, 1183–1189. [Google Scholar] [CrossRef]
- Sasaki, Y.; Shimada, T.; Iizuka, S.; Suzuki, W.; Makihara, H.; Teraoka, R.; Tsuneyama, K.; Hokao, R.; Aburada, M. Effects of bezafibrate in nonalcoholic steatohepatitis model mice with monosodium glutamate-induced metabolic syndrome. Eur. J. Pharmacol. 2011, 662, 1–8. [Google Scholar] [CrossRef]
- Chalasani, N.; Younossi, Z.; Lavine, J.E.; Charlton, M.; Cusi, K.; Rinella, M.; Harrison, S.A.; Brunt, E.M.; Sanyal, A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018, 67, 328–357. [Google Scholar] [CrossRef]
- Lee, Y.H.; Kim, J.H.; Kim, S.R.; Jin, H.Y.; Rhee, E.J.; Cho, Y.M.; Lee, B.W. Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness. J. Korean Med. Sci. 2017, 32, 60–69. [Google Scholar] [CrossRef]
- Nakagami, H.; Shimamura, M.; Miyake, T.; Shimosato, T.; Minobe, N.; Moritani, T.; Kiomy Osako, M.; Nakagami, F.; Koriyama, H.; Kyutoku, M.; et al. Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet. Mol. Med. Rep. 2012, 5, 37–40. [Google Scholar] [CrossRef] [Green Version]
- Zarei, M.; Barroso, E.; Palomer, X.; Dai, J.; Rada, P.; Quesada-López, T.; Escolà-Gil, J.C.; Cedó, L.; Zali, M.R.; Molaei, M.; et al. Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease. Mol. Metab. 2018, 8, 117–131. [Google Scholar] [CrossRef] [PubMed]
- CymaBay Therapeutics. CymaBay Therapeutics Reports Topline 12-Week Data from an Ongoing Phase 2b Study of Seladelpar in Patients with Nonalcoholic Steatohepatitis; 2019. Available online: https://www.globenewswire.com/news-release/2019/06/11/1866763/0/en/CymaBay-Therapeutics-Reports-Topline-12-Week-Data-from-an-Ongoing-Phase-2b-Study-of-Seladelpar-in-Patients-with-Nonalcoholic-Steatohepatitis.html (accessed on 10 December 2021).
- Goyal, O.; Nohria, S.; Goyal, P.; Kaur, J.; Sharma, S.; Sood, A.; Chhina, R.S. Saroglitazar in patients with non-alcoholic fatty liver disease and diabetic dyslipidemia: A prospective, observational, real world study. Sci. Rep. 2020, 10, 21117. [Google Scholar] [CrossRef] [PubMed]
- Gawrieh, S.; Noureddin, M.; Loo, N.; Mohseni, R.; Awasty, V.; Cusi, K.; Kowdley, K.V.; Lai, M.; Schiff, E.; Parmar, D.; et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology 2021, 74, 1809–1824. [Google Scholar] [CrossRef] [PubMed]
- Francque, S.M.; Bedossa, P.; Ratziu, V.; Anstee, Q.M.; Bugianesi, E.; Sanyal, A.J.; Loomba, R.; Harrison, S.A.; Balabanska, R.; Mateva, L.; et al. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N. Engl. J. Med. 2021, 385, 1547–1558. [Google Scholar] [CrossRef]
- Harrison, S.A.; Alkhouri, N.; Davison, B.A.; Sanyal, A.; Edwards, C.; Colca, J.R.; Lee, B.H.; Loomba, R.; Cusi, K.; Kolterman, O.; et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2020, 72, 613–626. [Google Scholar] [CrossRef]
- Fukunaga, T.; Zou, W.; Rohatgi, N.; Colca, J.R.; Teitelbaum, S.L. An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss. J. Bone Miner. Res. 2015, 30, 481–488. [Google Scholar] [CrossRef] [Green Version]
- Jacques, V.; Bolze, S.; Hallakou-Bozec, S.; Czarnik, A.W.; Divakaruni, A.S.; Fouqueray, P.; Murphy, A.N.; Van der Ploeg, L.H.T.; DeWitt, S. Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity. Hepatol. Commun. 2021, 5, 1412–1425. [Google Scholar] [CrossRef]
- El, K.; Gray, S.M.; Capozzi, M.E.; Knuth, E.R.; Jin, E.; Svendsen, B.; Clifford, A.; Brown, J.L.; Encisco, S.E.; Chazotte, B.M.; et al. GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells. Sci. Adv. 2021, 7, eabf1948. [Google Scholar] [CrossRef]
- Wang, X.C.; Gusdon, A.M.; Liu, H.; Qu, S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J. Gastroenterol. 2014, 20, 14821–14830. [Google Scholar] [CrossRef]
- Samson, S.L.; Sathyanarayana, P.; Jogi, M.; Gonzalez, E.V.; Gutierrez, A.; Krishnamurthy, R.; Muthupillai, R.; Chan, L.; Bajaj, M. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 2011, 54, 3093–3100. [Google Scholar] [CrossRef] [Green Version]
- Newsome, P.N.; Buchholtz, K.; Cusi, K.; Linder, M.; Okanoue, T.; Ratziu, V.; Sanyal, A.J.; Sejling, A.S.; Harrison, S.A.; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2021, 384, 1113–1124. [Google Scholar] [CrossRef] [PubMed]
- Liava, C.; Sinakos, E. Semaglutide for nonalcoholic steatohepatitis: Closer to a solution? Hepatobiliary Surg. Nutr. 2021, 10, 541–544. [Google Scholar] [CrossRef] [PubMed]
- Dutour, A.; Abdesselam, I.; Ancel, P.; Kober, F.; Mrad, G.; Darmon, P.; Ronsin, O.; Pradel, V.; Lesavre, N.; Martin, J.C.; et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: A prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes. Metab. 2016, 18, 882–891. [Google Scholar] [CrossRef] [PubMed]
- Sofogianni, A.; Filippidis, A.; Chrysavgis, L.; Tziomalos, K.; Cholongitas, E. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J. Hepatol. 2020, 12, 493–505. [Google Scholar] [CrossRef]
- Cusi, K.; Sattar, N.; García-Pérez, L.E.; Pavo, I.; Yu, M.; Robertson, K.E.; Karanikas, C.A.; Haupt, A. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: A post hoc analysis of the AWARD programme. Diabet. Med. 2018, 35, 1434–1439. [Google Scholar] [CrossRef]
- Kuchay, M.S.; Krishan, S.; Mishra, S.K.; Choudhary, N.S.; Singh, M.K.; Wasir, J.S.; Kaur, P.; Gill, H.K.; Bano, T.; Farooqui, K.J.; et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: Randomised controlled trial (D-LIFT trial). Diabetologia 2020, 63, 2434–2445. [Google Scholar] [CrossRef]
- Koutsovasilis, A.; Sotiropoulos, A.; Pappa, M.; Apostolou, O.; Binikos, I.; Kordinas, V.; Papadaki, D.; Tamvakos, I.; Bousboulas, S. Effectiveness of lixisenatide in nonalcoholic fatty liver disease in patients with type 2 diabetes after an acute coronary syndrome compared to sitagliptin and pioglitazone. In Proceedings of the EASD Virtual Meeting 2016, Munich, Germany, 14 September 2016. [Google Scholar]
- Armstrong, M.J.; Gaunt, P.; Aithal, G.P.; Barton, D.; Hull, D.; Parker, R.; Hazlehurst, J.M.; Guo, K.; LEAN Trial Team; Abouda, G.; 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. [Google Scholar] [CrossRef] [Green Version]
- Ghosal, S.; Datta, D.; Sinha, B. A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D). Sci. Rep. 2021, 11, 22063. [Google Scholar] [CrossRef]
- Thondam, S.K.; Cuthbertson, D.J.; Wilding, J.P.H. The influence of Glucose-dependent Insulinotropic Polypeptide (GIP) on human adipose tissue and fat metabolism: Implications for obesity, type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD). Peptides 2020, 125, 170208. [Google Scholar] [CrossRef]
- Hartman, M.L.; Sanyal, A.J.; Loomba, R.; Wilson, J.M.; Nikooienejad, A.; Bray, R.; Karanikas, C.A.; Duffin, K.L.; Robins, D.A.; Haupt, A. Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes. Diabetes Care 2020, 43, 1352–1355. [Google Scholar] [CrossRef]
- Gastaldelli, A.; Cusi, K.; Landó, F.; Bray, R.; Brouwers, B.; Rodríguez, Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in patients with type 2 diabetes (SURPASS-3 MRI). In Proceedings of the EASD Virtual Meeting 2021, Virtual, 30 September 2021. [Google Scholar]
- Pocai, A. Action and therapeutic potential of oxyntomodulin. Mol. Metab. 2013, 3, 241–251. [Google Scholar] [CrossRef] [PubMed]
- Boland, M.L.; Laker, R.C.; Mather, K.; Nawrocki, A.; Oldham, S.; Boland, B.B.; Lewis, H.; Conway, J.; Naylor, J.; Guionaud, S.; et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2020, 2, 413–431. [Google Scholar] [CrossRef] [PubMed]
- Nahra, R.; Wang, T.; Gadde, K.M.; Oscarsson, J.; Stumvoll, M.; Jermutus, L.; Hirshberg, B.; Ambery, P. Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults with Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study. Diabetes Care 2021, 44, 1433–1442. [Google Scholar] [CrossRef] [PubMed]
- Jung, S.Y.; Park, Y.J.; Lee, J.S.; Kim, E.J.; Lee, Y.M.; Kim, Y.H.; Trautmann, M.; Kwon, S.C. Potent Cholesterol Lowering Effect by HM12525A, A Novel Long-acting GLP-1/Glucagon Dual Receptor Agonist. In Proceedings of the American Diabetes Association’s (ADA) 76th Scientific Sessions, New Orleans, LA, USA, 10–14 June 2016. [Google Scholar]
- Pfizer Inc. Available online: https://www.pfizer.com/ (accessed on 10 December 2021).
- Hanmi Pharmaceutical Co., Ltd. Available online: http://www.hanmipharm.com/ehanmi/handler/Home-Start (accessed on 10 December 2021).
- Kim, J.K.; Lee, J.S.; Park, E.; Lee, J.; Bae, S.; Kim, D.; Choi, I.C. HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist, Exhibits Anti-inflammatory and Fibrotic Effects in AMLN/TAA–Induced Liver Inflammation and Fibrosis Mice. Diabetes 2020, 69, 1804-P. [Google Scholar] [CrossRef]
- Janssen, P.; Rotondo, A.; Mulé, F.; Tack, J. Review article: A comparison of glucagon-like peptides 1 and 2. Aliment. Pharmacol. Ther. 2013, 37, 18–36. [Google Scholar] [CrossRef] [Green Version]
- Hu, Y.-X. Therapeutic effect of teduglutide on non-alcoholic fatty liver disease in rats. World Chin. J. Dig. 2016, 24, 1009. [Google Scholar] [CrossRef]
- Alam, S.; Ghosh, J.; Mustafa, G.; Kamal, M.; Ahmad, N. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: A 1-year randomized control trial. Hepat. Med. 2018, 10, 23–31. [Google Scholar] [CrossRef] [Green Version]
- Aktaş, A.; Ozan, Z.T. The efficacy and safety of vildagliptin treatment for nonalcoholic fatty liver disease in type 2 diabetes mellitus. Cumhur. Med. J. 2020, 42, 491–499. [Google Scholar] [CrossRef]
- Li, J.J.; Zhang, P.; Fan, B.; Guo, X.L.; Zheng, Z.S. The efficacy of saxagliptin in T2DM patients with non-alcoholic fatty liver disease: Preliminary data. Rev. Assoc. Med. Bras. 2019, 65, 33–37. [Google Scholar] [CrossRef]
- Hattori, S.; Nomoto, K.; Suzuki, T.; Hayashi, S. Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Diabetol. Metab. Syndr. 2021, 13, 28. [Google Scholar] [CrossRef]
- Gupta, V.K. Teneligliptin Significantly Reduces Liver Fat Content (LFC) and Delays Progression of NASH in Type 2 Diabetes Mellitus Patients. Diabetes 2019, 68, 1029-P. [Google Scholar] [CrossRef]
- Mashitani, T.; Noguchi, R.; Okura, Y.; Namisaki, T.; Mitoro, A.; Ishii, H.; Nakatani, T.; Kikuchi, E.; Moriyasu, H.; Matsumoto, M.; et al. Efficacy of alogliptin in preventing non-alcoholic fatty liver disease progression in patients with type 2 diabetes. Biomed. Rep. 2016, 4, 183–187. [Google Scholar] [CrossRef]
- Dos Santos, L.R.; Duarte, M.L.; Peccin, M.S.; Gagliardi, A.R.T.; Melnik, T. Dipeptidyl Peptidase IV Inhibitors for Nonalcoholic Fatty Liver Disease—Systematic Review and Metanalysis. Curr. Diabetes Rev. 2021, 17, e101120187811. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Park, H.; Bae, E.J. Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: A comparative study. Korean J. Physiol. Pharmacol. 2019, 23, 459–466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sakai, Y.; Nagashimada, M.; Nagata, N.; Ni, Y.; Kaneko, S.; Ota, T. Dipeptidyl peptidase-4 inhibitor anagliptin alleviates lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice. In Proceedings of the EASD Virtual Meeting 2015, Stockholm, Sweden, 15 September 2015. [Google Scholar]
- Kawakubo, M.; Tanaka, M.; Ochi, K.; Watanabe, A.; Saka-Tanaka, M.; Kanamori, Y.; Yoshioka, N.; Yamashita, S.; Goto, M.; Itoh, M.; et al. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci. Rep. 2020, 10, 983. [Google Scholar] [CrossRef] [PubMed]
- Wang, G.; Wu, B.; Zhang, L.; Jin, X.; Wang, K.; Xu, W.; Zhang, B.; Wang, H. The protective effects of trelagliptin on high-fat diet-induced nonalcoholic fatty liver disease in mice. J. Biochem. Mol. Toxicol. 2021, 35, e22696. [Google Scholar] [CrossRef]
- Choi, S.H.; Leem, J.; Park, S.; Lee, C.K.; Park, K.G.; Lee, I.K. Gemigliptin ameliorates Western-diet-induced metabolic syndrome in mice. Can. J. Physiol. Pharmacol. 2017, 95, 129–139. [Google Scholar] [CrossRef] [Green Version]
- Klein, T.; Fujii, M.; Sandel, J.; Shibazaki, Y.; Wakamatsu, K.; Mark, M.; Yoneyama, H. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med. Mol. Morphol. 2014, 47, 137–149. [Google Scholar] [CrossRef]
- Saisho, Y. SGLT2 Inhibitors: The Star in the Treatment of Type 2 Diabetes? Diseases 2020, 8, 14. [Google Scholar] [CrossRef]
- Wu, P.; Wen, W.; Li, J.; Xu, J.; Zhao, M.; Chen, H.; Sun, J. Systematic Review and Meta-Analysis of Randomized Controlled Trials on the Effect of SGLT2 Inhibitor on Blood Leptin and Adiponectin Level in Patients with Type 2 Diabetes. Horm. Metab. Res. 2019, 51, 487–494. [Google Scholar] [CrossRef] [Green Version]
- Sumida, Y.; Yoneda, M.; Tokushige, K.; Kawanaka, M.; Fujii, H.; Yoneda, M.; Imajo, K.; Takahashi, H.; Ono, M.; Nozaki, Y.; et al. Hepatoprotective Effect of SGLT2 Inhibitor on Nonalcoholic Fatty Liver Disease. Diabetes Res. Open Access 2020, 2, 17–25. [Google Scholar] [CrossRef] [Green Version]
- Ribeiro Dos Santos, L.; Baer Filho, R. Treatment of nonalcoholic fatty liver disease with dapagliflozin in non-diabetic patients. Metabol. Open 2020, 5, 100028. [Google Scholar] [CrossRef] [PubMed]
- Taheri, H.; Malek, M.; Ismail-Beigi, F.; Zamani, F.; Sohrabi, M.; Reza Babaei, M.; Khamseh, M.E. Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Adv. Ther. 2020, 37, 4697–4708. [Google Scholar] [CrossRef] [PubMed]
- Itani, T.; Ishihara, T. Efficacy of canagliflozin against nonalcoholic fatty liver disease: A prospective cohort study. Obes. Sci. Pract. 2018, 4, 477–482. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prikhodko, V.A.; Sysoev, Y.I.; Poveryaeva, M.A.; Bunyat, A.V.; Karev, V.E.; Ivkin, D.Y.; Sukhanov, D.S.; Shustov, E.B.; Okovityi, S.V. Effects of Empagliflozin and L-Ornithine L-Aspartate on Behavior, Cognitive Functions, and Physical Performance in Mice with Experimentally Induced Steatohepatitis. Bull. RSMU 2020, 3, 49–57. [Google Scholar] [CrossRef]
- Takahashi, H.; Kessoku, T.; Kawanaka, M.; Nonaka, M.; Hyogo, H.; Fujii, H.; Nakajima, T.; Imajo, K.; Tanaka, K.; Kubotsu, Y.; et al. Ipragliflozin Improves the Hepatic Outcomes of Patients with Diabetes with NAFLD. Hepatol. Commun. 2021; online ahead of print. [Google Scholar] [CrossRef]
- Wilkison, B.; Cheatham, B.; Walker, S. Remogliflozin Etabonate Reduces FIB-4 and NAFLD Fibrosis Scores in Type 2 Diabetic Subjects. Hepatology 2016, 64, 548A. [Google Scholar]
- Gallo, S.; Calle, R.A.; Terra, S.G.; Pong, A.; Tarasenko, L.; Raji, A. Effects of Ertugliflozin on Liver Enzymes in Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis of Phase 3 Trials. Diabetes Ther. 2020, 11, 1849–1860. [Google Scholar] [CrossRef]
- Shibuya, T.; Fushimi, N.; Kawai, M.; Yoshida, Y.; Hachiya, H.; Ito, S.; Kawai, H.; Ohashi, N.; Mori, A. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective randomized controlled pilot study. Diabetes Obes. Metab. 2018, 20, 438–442. [Google Scholar] [CrossRef]
- Sumida, Y.; Murotani, K.; Saito, M.; Tamasawa, A.; Osonoi, Y.; Yoneda, M.; Osonoi, T. Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective, single-arm trial (LEAD trial). Hepatol. Res. 2019, 49, 64–71. [Google Scholar] [CrossRef] [Green Version]
- Yoneda, M.; Honda, Y.; Ogawa, Y.; Kessoku, T.; Kobayashi, T.; Imajo, K.; Ozaki, A.; Nogami, A.; Taguri, M.; Yamanaka, T.; et al. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): A randomized prospective open-label controlled trial. BMJ Open Diabetes Res. Care 2021, 9, e001990. [Google Scholar] [CrossRef]
- He, Y.L.; Haynes, W.; Meyers, C.D.; Amer, A.; Zhang, Y.; Mahling, P.; Mendonza, A.E.; Ma, S.; Chutkow, W.; Bachman, E. The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes. Diabetes Obes. Metab. 2019, 21, 1311–1321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Harrison, S.A.; Manghi, F.P.; Smith, W.B.; Alpenidze, D.; Aizenberg, D.; Burggraaf, K.; Chen, C.-Y.; Zuckerman, E.; Ravussin, E.; Charatcharoenwitthaya, P.; et al. LIK066 (Licogliflozin), an SGLT1/2 Inhibitor, Robustly Decreases ALT and Improves Markers of Hepatic and Metabolic Health in Patients with Non-Alcoholic Fatty Liver Disease: Interim Analysis of a 12-Week, Randomized, Placebo-Controlled, Phase 2a Study. In Proceedings of the Liver Meeting 2019, Boston, MA, USA, 8–12 November 2019. [Google Scholar]
- Honda, Y.; Ozaki, A.; Iwaki, M.; Kobayashi, T.; Nogami, A.; Kessoku, T.; Ogawa, Y.; Tomeno, W.; Imajo, K.; Yoneda, M.; et al. Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice. J. Pharmacol. Sci. 2021, 147, 176–183. [Google Scholar] [CrossRef] [PubMed]
- Iogna Prat, L.; Tsochatzis, E.A. The effect of antidiabetic medications on non-alcoholic fatty liver disease (NAFLD). Hormones 2018, 17, 219–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hajiaghamohammadi, A.A.; Miroliaee, A.; Samimi, R.; Alborzi, F.; Ziaee, A. A Comparison of Ezetimibe and Acarbose in Decreasing Liver Transaminase in Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. Govaresh 2013, 18, 186–190. [Google Scholar]
- Komatsu, M.; Tanaka, N.; Kimura, T.; Fujimori, N.; Sano, K.; Horiuchi, A.; Sugiura, A.; Yamazaki, T.; Shibata, S.; Joshita, S.; et al. Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients. Hepatol. Res. 2018, 48, 1092–1098. [Google Scholar] [CrossRef]
- Kim, J.W.; Lee, Y.J.; You, Y.H.; Moon, M.K.; Yoon, K.H.; Ahn, Y.B.; Ko, S.H. Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes. J. Cell. Biochem. 2018; online ahead of print. [Google Scholar] [CrossRef]
- Meroni, M.; Longo, M.; Dongiovanni, P. The Role of Probiotics in Nonalcoholic Fatty Liver Disease: A New Insight into Therapeutic Strategies. Nutrients 2019, 11, 2642. [Google Scholar] [CrossRef] [Green Version]
- Malaguarnera, M.; Vacante, M.; Antic, T.; Giordano, M.; Chisari, G.; Acquaviva, R.; Mastrojeni, S.; Malaguarnera, G.; Mistretta, A.; Li Volti, G.; et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig. Dis. Sci. 2012, 57, 545–553. [Google Scholar] [CrossRef]
- Vajro, P.; Mandato, C.; Licenziati, M.R.; Franzese, A.; Vitale, D.F.; Lenta, S.; Caropreso, M.; Vallone, G.; Meli, R. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J. Pediatr. Gastroenterol. Nutr. 2011, 52, 740–743. [Google Scholar] [CrossRef] [Green Version]
- Nabavi, S.; Rafraf, M.; Somi, M.H.; Homayouni-Rad, A.; Asghari-Jafarabadi, M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J. Dairy Sci. 2014, 97, 7386–7393. [Google Scholar] [CrossRef]
- Román, E.; Nieto, J.C.; Gely, C.; Vidal, S.; Pozuelo, M.; Poca, M.; Juárez, C.; Guarner, C.; Manichanh, C.; Soriano, G. Effect of a Multistrain Probiotic on Cognitive Function and Risk of Falls in Patients with Cirrhosis: A Randomized Trial. Hepatol. Commun. 2019, 3, 632–645. [Google Scholar] [CrossRef] [Green Version]
- Ahn, S.B.; Jun, D.W.; Kang, B.K.; Lim, J.H.; Lim, S.; Chung, M.J. Randomized, Double-blind, Placebo-controlled Study of a Multispecies Probiotic Mixture in Nonalcoholic Fatty Liver Disease. Sci. Rep. 2019, 9, 5688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kobyliak, N.; Abenavoli, L.; Mykhalchyshyn, G.; Kononenko, L.; Boccuto, L.; Kyriienko, D.; Dynnyk, O. A Multi-strain Probiotic Reduces the Fatty Liver Index, Cytokines and Aminotransferase levels in NAFLD Patients: Evidence from a Randomized Clinical Trial. J. Gastrointestin Liver Dis. 2018, 27, 41–49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, Y.Y.; Li, L.; Yu, C.H.; Shen, Z.; Chen, L.H.; Li, Y.M. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World J. Gastroenterol. 2013, 19, 6911–6918. [Google Scholar] [CrossRef] [PubMed]
- Gao, X.; Zhu, Y.; Wen, Y.; Liu, G.; Wan, C. Efficacy of probiotics in non-alcoholic fatty liver disease in adult and children: A meta-analysis of randomized controlled trials. Hepatol. Res. 2016, 46, 1226–1233. [Google Scholar] [CrossRef]
- Liu, Y.T.; Li, Y.Q.; Wang, Y.Z. Protective effect of Saccharomyces boulardii against intestinal mucosal barrier injury in rats with nonalcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 2016, 24, 921–926. (In Chinese) [Google Scholar] [CrossRef]
- Yamauchi, R.; Takedatsu, H.; Yokoyama, K.; Yamauchi, E.; Kawashima, M.; Tsuchiya, N.; Takata, K.; Tanaka, T.; Morihara, D.; Takeyama, Y.; et al. Synergistic effect of clostridium butyricum miyairi on rifaximin in mice model of non-alcoholic steatohepatitis by methionine choline-deficient diet. J. Hepatol. 2020, 73, S401–S652. [Google Scholar] [CrossRef]
- Abdel Monem, S.M. Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals. Euroasian J. Hepatogastroenterol. 2017, 7, 101–106. [Google Scholar] [CrossRef] [Green Version]
- Li, C.; Nie, S.P.; Zhu, K.X.; Ding, Q.; Li, C.; Xiong, T.; Xie, M.Y. Lactobacillus plantarum NCU116 improves liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease. Food Funct. 2014, 5, 3216–3223. [Google Scholar] [CrossRef]
- Yao, F.; Jia, R.; Huang, H.; Yu, Y.; Mei, L.; Bai, L.; Ding, Y.; Zheng, P. Effect of Lactobacillus paracasei N1115 and fructooligosaccharides in nonalcoholic fatty liver disease. Arch. Med. Sci. 2019, 15, 1336–1344. [Google Scholar] [CrossRef]
- Xin, J.; Zeng, D.; Wang, H.; Ni, X.; Yi, D.; Pan, K.; Jing, B. Preventing non-alcoholic fatty liver disease through Lactobacillus johnsonii BS15 by attenuating inflammation and mitochondrial injury and improving gut environment in obese mice. Appl. Microbiol. Biotechnol. 2014, 98, 6817–6829. [Google Scholar] [CrossRef]
- Ting, W.J.; Kuo, W.W.; Hsieh, D.J.; Yeh, Y.L.; Day, C.H.; Chen, Y.H.; Chen, R.J.; Padma, V.V.; Chen, Y.H.; Huang, C.Y. Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-β Suppression. Int. J. Mol. Sci. 2015, 16, 25881–25896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aller, R.; De Luis, D.A.; Izaola, O.; Conde, R.; Gonzalez Sagrado, M.; Primo, D.; De La Fuente, B.; Gonzalez, J. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: A double blind randomized clinical trial. Eur. Rev. Med. Pharmacol. Sci. 2011, 15, 1090–1095. [Google Scholar] [PubMed]
- Famouri, F.; Shariat, Z.; Hashemipour, M.; Keikha, M.; Kelishadi, R. Effects of Probiotics on Nonalcoholic Fatty Liver Disease in Obese Children and Adolescents. J. Pediatr. Gastroenterol. Nutr. 2017, 64, 413–417. [Google Scholar] [CrossRef] [PubMed]
- Wong, V.W.; Won, G.L.; Chim, A.M.; Chu, W.C.; Yeung, D.K.; Li, K.C.; Chan, H.L. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann. Hepatol. 2013, 12, 256–262. [Google Scholar] [CrossRef]
- Alisi, A.; Bedogni, G.; Baviera, G.; Giorgio, V.; Porro, E.; Paris, C.; Giammaria, P.; Reali, L.; Anania, F.; Nobili, V. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 2014, 39, 1276–1285. [Google Scholar] [CrossRef]
- Ezquer, M.; Ezquer, F.; Ricca, M.; Allers, C.; Conget, P. Intravenous administration of multipotent stromal cells prevents the onset of non-alcoholic steatohepatitis in obese mice with metabolic syndrome. J. Hepatol. 2011, 55, 1112–1120. [Google Scholar] [CrossRef]
- Hsu, M.J.; Karkossa, I.; Schäfer, I.; Christ, M.; Kühne, H.; Schubert, K.; Rolle-Kampczyk, U.E.; Kalkhof, S.; Nickel, S.; Seibel, P.; et al. Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH. Biomedicines 2020, 8, 350. [Google Scholar] [CrossRef]
- Wang, H.; Wang, D.; Yang, L.; Wang, Y.; Jia, J.; Na, D.; Chen, H.; Luo, Y.; Liu, C. Compact bone-derived mesenchymal stem cells attenuate nonalcoholic steatohepatitis in a mouse model by modulation of CD4 cells differentiation. Int. Immunopharmacol. 2017, 42, 67–73. [Google Scholar] [CrossRef] [Green Version]
- Chien, Y.; Huang, C.S.; Lin, H.C.; Lu, K.H.; Tsai, P.H.; Lai, Y.H.; Chen, K.H.; Lee, S.D.; Huang, Y.H.; Wang, C.Y. Improvement of non-alcoholic steatohepatitis by hepatocyte-like cells generated from iPSCs with Oct4/Sox2/Klf4/Parp1. Oncotarget 2018, 9, 18594–18606. [Google Scholar] [CrossRef] [Green Version]
- Overi, D.; Carpino, G.; Franchitto, A.; Onori, P.; Gaudio, E. Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis. Cells 2020, 9, 590. [Google Scholar] [CrossRef] [Green Version]
- Nevens, F.; Gustot, T.; Laterre, P.F.; Lasser, L.L.; Haralampiev, L.E.; Vargas, V.; Lyubomirova, D.; Albillos, A.; Najimi, M.; Michel, S.; et al. A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation. JHEP Rep. 2021, 3, 100291. [Google Scholar] [CrossRef] [PubMed]
- Iqbal, U.; Perumpail, B.J.; John, N.; Sallam, S.; Shah, N.D.; Kwong, W.; Cholankeril, G.; Kim, D.; Ahmed, A. Judicious Use of Lipid Lowering Agents in the Management of NAFLD. Diseases 2018, 6, 87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oniciu, D.C.; Hashiguchi, T.; Shibazaki, Y.; Bisgaier, C.L. Gemcabene downregulates inflammatory, lipid-altering and cell-signaling genes in the STAM™ model of NASH. PLoS ONE 2018, 13, e0194568. [Google Scholar] [CrossRef] [PubMed]
- Sanjay, K.V.; Vishwakarma, S.; Zope, B.R.; Mane, V.S.; Mohire, S.; Dhakshinamoorthy, S. ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score. Curr. Res. Pharmacol. Drug Discov. 2021, 2, 100051. [Google Scholar] [CrossRef] [PubMed]
- Stanley, T.L.; Feldpausch, M.N.; Oh, J.; Branch, K.L.; Lee, H.; Torriani, M.; Grinspoon, S.K. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: A randomized clinical trial. JAMA 2014, 312, 380–389. [Google Scholar] [CrossRef]
- Theratechnologies Inc. Available online: https://www.theratech.com/ (accessed on 10 December 2021).
- Wei, X.; Wang, C.; Hao, S.; Song, H.; Yang, L. The Therapeutic Effect of Berberine in the Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis. Evid.-Based Complementary Altern. Med. 2016, 2016, 3593951. [Google Scholar] [CrossRef] [Green Version]
- Yin, J.; Ye, J.; Jia, W. Effects and mechanisms of berberine in diabetes treatment. Acta Pharm. Sin. B 2012, 2, 327–334. [Google Scholar] [CrossRef] [Green Version]
- Simental-Mendía, M.; Sánchez-García, A.; Simental-Mendía, L.E. Effect of ursodeoxycholic acid on liver markers: A systematic review and meta-analysis of randomized placebo-controlled clinical trials. Br. J. Clin. Pharmacol. 2020, 86, 1476–1488. [Google Scholar] [CrossRef]
- Zhang, W.; Tang, Y.; Huang, J.; Hu, H. Efficacy of ursodeoxycholic acid in nonalcoholic fatty liver disease: An updated meta-analysis of randomized controlled trials. Asia Pac. J. Clin. Nutr. 2020, 29, 696–705. [Google Scholar] [CrossRef]
- Harrison, S.A.; Gunn, N.; Neff, G.W.; Kohli, A.; Liu, L.; Flyer, A.; Goldkind, L.; Di Bisceglie, A.M. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat. Commun. 2021, 12, 5503. [Google Scholar] [CrossRef]
- Kowdley, K.V.; Butler, P.; Cubberley, S.; Hand, A.L.; Jenders, R.A.; Kroon, J.; Leibowitz, M.; Moore, A.C.; Guyer, B. Miricorilant, a Selective GR Modulator, Induced a Rapid and Significant Reduction in Liver Fat Content in a Randomized, Placebo-Controlled Phase 2a Study in Patients with Non-Alcoholic Steatohepatitis. In Proceedings of the Liver Meeting 2021, Virtual, 12–15 November 2021. [Google Scholar]
- Li, F.; Jiang, M.; Ma, M.; Chen, X.; Zhang, Y.; Zhang, Y.; Yu, Y.; Cui, Y.; Chen, J.; Zhao, H.; et al. Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice. Acta Pharm. Sin. B 2021, in press, corrected proof. [CrossRef]
- Walczak, R.; Carole, B.; Benoit, N.; Descamps, E.; Nathalie, D.; Meghien, S.; Hum, D.; Staels, B.; Friedman, S.; Loomba, R.; et al. Elafibranor and nitazoxanide synergize to reduce fibrosis in a NASH model. J. Hepatol. 2018, 68, S105–S364. [Google Scholar] [CrossRef]
- Glal, K.A.M.; Abd-Elsalam, S.M.; Mostafa, T.M. Nitazoxanide versus rifaximin in preventing the recurrence of hepatic encephalopathy: A randomized double-blind controlled trial. J. Hepato-Biliary-Pancreat. Sci. 2021, 28, 812–824. [Google Scholar] [CrossRef] [PubMed]
- Flores-Contreras, L.; Sandoval-Rodríguez, A.S.; Mena-Enriquez, M.G.; Lucano-Landeros, S.; Arellano-Olivera, I.; Alvarez-Álvarez, A.; Sanchez-Parada, M.G.; Armendáriz-Borunda, J. Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol. 2014, 14, 131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cui, Y.; Zhang, M.; Leng, C.; Blokzijl, T.; Jansen, B.H.; Dijkstra, G.; Faber, K.N. Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells 2020, 9, 775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Poo, J.L.; Torre, A.; Aguilar-Ramírez, J.R.; Cruz, M.; Mejía-Cuán, L.; Cerda, E.; Velázquez, A.; Patiño, A.; Ramírez-Castillo, C.; Cisneros, L.; et al. Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study. Hepatol. Int. 2020, 14, 817–827. [Google Scholar] [CrossRef]
- Matsuda, K.; Iwaki, Y. MN-001 (tipelukast), a novel, orally bioavailable drug, reduces fibrosis and inflammation and down-regulates TIMP-1, collagen Type 1 and LOXL2 mRNA overexpression in an advanced NASH (non-alcoholic steatohepatitis) model. In Proceedings of the Liver Meeting 2014, Boston, MA, USA, 7–11 November 2014. [Google Scholar]
- Yang, M.; Zhang, C.Y. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World J. Gastroenterol. 2021, 27, 677–691. [Google Scholar] [CrossRef]
- Widjaja, A.A.; Singh, B.K.; Adami, E.; Viswanathan, S.; Dong, J.; D’Agostino, G.A.; Ng, B.; Lim, W.W.; Tan, J.; Paleja, B.S.; et al. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology 2019, 157, 777–792.e14. [Google Scholar] [CrossRef] [Green Version]
- Zai, W.; Chen, W.; Liu, H.; Ju, D. Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications. Biomedicines 2021, 9, 1912. [Google Scholar] [CrossRef]
- Stemmer, S.M.; Manojlovic, N.S.; Marinca, M.V.; Petrov, P.; Cherciu, N.; Ganea, D.; Ciuleanu, T.E.; Pusca, I.A.; Beg, M.S.; Purcell, W.T.; et al. Namodenoson in Advanced Hepatocellular Carcinoma and Child-Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial. Cancers 2021, 13, 187. [Google Scholar] [CrossRef]
- Ferramosca, A.; Di Giacomo, M.; Zara, V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J. Gastroenterol. 2017, 23, 4146–4157. [Google Scholar] [CrossRef]
- Ionis Pharmaceuticals, Inc. Available online: https://www.ionispharma.com/ (accessed on 10 December 2021).
- Lawitz, E.; Hassanein, T.; Denham, D.; Waters, M.; Borg, B.; Mille, G.; Scott, D.; Miksztal, A.; Culwell, J.; Ellis, D.; et al. Efficacy Signals of 4-Week Oral DUR-928 in NASH Subjects. In Proceedings of the Digital International Liver Congress 2021, Virtual, 23–26 June 2021. [Google Scholar]
- Konuma, K.; Itoh, M.; Suganami, T.; Kanai, S.; Nakagawa, N.; Sakai, T.; Kawano, H.; Hara, M.; Kojima, S.; Izumi, Y.; et al. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice. PLoS ONE 2015, 10, e0121528. [Google Scholar] [CrossRef] [PubMed]
- Sojoodi, M.; Wang, Y.; Erstad, D.J.; Caravan, P.; Lanuti, M.; Qadan, M.; Fuchs, B.C.; Hoang, K.; Or, Y.S.; Jiang, L.; et al. EDP-297, a novel and potent fxr agonist, exhibit robust antifibrotic effects with significant liver function in a rat model of non-alcoholic steatohepatitis. J. Hepatol. 2020, 73, S401–S652. [Google Scholar] [CrossRef]
- Ma, Y.; Huang, Y.; Yan, L.; Gao, M.; Liu, D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm. Res. 2013, 30, 1447–1457. [Google Scholar] [CrossRef] [PubMed]
- Fraile, J.M.; Palliyil, S.; Barelle, C.; Porter, A.J.; Kovaleva, M. Non-Alcoholic Steatohepatitis (NASH)—A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. Drug Des. Dev. Ther. 2021, 15, 3997–4009. [Google Scholar] [CrossRef]
- Aithal, G.P.; Thomas, J.A.; Kaye, P.V.; Lawson, A.; Ryder, S.D.; Spendlove, I.; Austin, A.S.; Freeman, J.G.; Morgan, L.; Webber, J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008, 135, 1176–1184. [Google Scholar] [CrossRef] [Green Version]
- Altimmune, Inc. Pemvidutide (ALT-801): Phase 1 12-Week Results. Available online: https://ir.altimmune.com/static-files/d3319658-9809-44ad-a729-05dd6a6bf4c5 (accessed on 10 December 2021).
- Tobita, H.; Sato, S.; Miyake, T.; Ishihara, S.; Kinoshita, Y. Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Curr. Ther. Res. Clin. Exp. 2017, 87, 13–19. [Google Scholar] [CrossRef]
- Lai, L.L.; Vethakkan, S.R.; Nik Mustapha, N.R.; Mahadeva, S.; Chan, W.K. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig. Dis. Sci. 2020, 65, 623–631. [Google Scholar] [CrossRef]
- Seko, Y.; Sumida, Y.; Tanaka, S.; Mori, K.; Taketani, H.; Ishiba, H.; Hara, T.; Okajima, A.; Umemura, A.; Nishikawa, T.; et al. Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol. Res. 2017, 47, 1072–1078. [Google Scholar] [CrossRef]
- Cusi, K.; Alkhouri, N.; Harrison, S.A.; Fouqueray, P.; Moller, D.E.; Hallakou-Bozec, S.; Bolze, S.; Grouin, J.M.; Jeannin Megnien, S.; Dubourg, J.; 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. Lancet Gastroenterol. Hepatol. 2021, 6, 889–902. [Google Scholar] [CrossRef]
- Chalasani, N.; Vuppalanchi, R.; Rinella, M.; Middleton, M.S.; Siddiqui, M.S.; Barritt, A.S., IV; Kolterman, O.; Flores, O.; Alonso, C.; Iruarrizaga-Lejarreta, M.; et al. Randomised clinical trial: A leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2018, 47, 1639–1651. [Google Scholar] [CrossRef]
- Simard, J.C.; Thibodeau, J.F.; Leduc, M.; Tremblay, M.; Laverdure, A.; Sarra-Bournet, F.; Gagnon, W.; Ouboudinar, J.; Gervais, L.; Felton, A.; et al. Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease. Sci Rep 2020, 10, 12778. [Google Scholar] [CrossRef] [PubMed]
- Puengel, T.; De Vos, S.; Hundertmark, J.; Kohlhepp, M.; Guldiken, N.; Pujuguet, P.; Auberval, M.; Marsais, F.; Shoji, K.F.; Saniere, L.; et al. The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis. J. Clin. Med. 2020, 9, 1140. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Liu, C.; Ruan, L. G-Protein-Coupled Receptors 120 Agonist III Improves Hepatic Inflammation and ER Stress in Steatohepatitis. Dig. Dis. Sci. 2021, 66, 1090–1096. [Google Scholar] [CrossRef]
- Teng, B.; Huang, C.; Cheng, C.L.; Udduttula, A.; Yu, X.F.; Liu, C.; Li, J.; Yao, Z.Y.; Long, J.; Miao, L.F.; et al. Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A. J. Hepatol. 2020, 73, 383–393. [Google Scholar] [CrossRef] [PubMed]
- Ookawara, M.; Matsuda, K.; Watanabe, M.; Moritoh, Y. The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight. J. Pharmacol. Exp. Ther. 2020, 375, 21–27. [Google Scholar] [CrossRef] [PubMed]
- Shafiq, M.; Walmann, T.; Nutalapati, V.; Gibson, C.; Zafar, Y. Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver. World J. Hepatol. 2020, 12, 1258–1266. [Google Scholar] [CrossRef]
- Jun, B.G.; Cheon, G.J. The utility of ezetimibe therapy in nonalcoholic fatty liver disease. Korean J. Intern. Med. 2019, 34, 284–285. [Google Scholar] [CrossRef] [Green Version]
- Kidron, M.; Perles, S.; Kaloti, R.; Ghantous, R.; Sandouka, S.F.; Malaabi, Y.; Safadi, R. Oral Insulin–Induced Reduction in Liver Fat Content in T2DM Patients with Nonalcoholic Steatohepatitis. Diabetes 2020, 69, 115-LB. [Google Scholar] [CrossRef]
- Cansby, E.; Nuñez-Durán, E.; Magnusson, E.; Amrutkar, M.; Booten, S.L.; Kulkarni, N.M.; Svensson, L.T.; Borén, J.; Marschall, H.U.; Aghajan, M.; et al. Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease. Cell. Mol. Gastroenterol. Hepatol. 2019, 7, 597–618. [Google Scholar] [CrossRef] [Green Version]
- Segal-Salto, M.; Barashi, N.; Katav, A.; Edelshtein, V.; Aharon, A.; Hashmueli, S.; George, J.; Maor, Y.; Pinzani, M.; Haberman, D.; et al. A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage. JHEP Rep. 2020, 2, 100064. [Google Scholar] [CrossRef] [Green Version]
- Safadi, R.; Braun, M.; Francis, A.; Milgrom, Y.; Massarwa, M.; Hakimian, D.; Hazou, W.; Issachar, A.; Harpaz, Z.; Farbstein, M.; et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment. Pharmacol. Ther. 2021, 54, 1405–1415. [Google Scholar] [CrossRef] [PubMed]
- Pliant Therapeutics. Available online: https://pliantrx.com/ (accessed on 10 December 2021).
- CohBar, Inc. Available online: https://www.cohbar.com/ (accessed on 10 December 2021).
- Cerenis Therapeutics. Results of the Phase I Study of Repeated and Increasing Doses to Assess CER-209 in NASH/NAFLD: Press Release; 2018. Available online: https://www.abionyx.com/images/pdfs/images/pr_cerenis_CER_209_ENG_final_e06d4.pdf (accessed on 10 December 2021).
- Hepion Pharmaceuticals. Available online: https://hepionpharma.com/ (accessed on 10 December 2021).
- Lipocine. Available online: https://www.lipocine.com/ (accessed on 10 December 2021).
- Gupte, A.A.; Sabek, O.M.; Fraga, D.; Minze, L.J.; Nishimoto, S.K.; Liu, J.Z.; Afshar, S.; Gaber, L.; Lyon, C.J.; Gaber, O.; et al. Osteocalcin protects against non-alcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 2020, 155, 4697–4705. [Google Scholar] [CrossRef] [Green Version]
- Sookoian, S.; Pirola, C.J.; Valenti, L.; Davidson, N.O. Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights from Systems Biology. Hepatology 2020, 72, 330–346. [Google Scholar] [CrossRef] [PubMed]
- Kumar, V.; Xin, X.; Ma, J.; Tan, C.; Osna, N.; Mahato, R.I. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv. Drug Deliv. Rev. 2021, 176, 113888. [Google Scholar] [CrossRef] [PubMed]
- Fang, Z.; Dou, G.; Wang, L. MicroRNAs in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int. J. Biol. Sci. 2021, 17, 1851–1863. [Google Scholar] [CrossRef]
- Wu, P.; Zhang, M.; Webster, N.J.G. Alternative RNA Splicing in Fatty Liver Disease. Front. Endocrinol. 2021, 12, 613213. [Google Scholar] [CrossRef]
- Bosch-Presegué, L.; Vaquero, A. Sirtuins in stress response: Guardians of the genome. Oncogene 2014, 33, 3764–3775. [Google Scholar] [CrossRef] [Green Version]
- Vachharajani, V.; McCall, C.E. Sirtuins: Potential therapeutic targets for regulating acute inflammatory response? Expert Opin. Ther. Targets 2020, 24, 489–497. [Google Scholar] [CrossRef]
- Zhu, Y.; Yan, Y.; Gius, D.R.; Vassilopoulos, A. Metabolic regulation of Sirtuins upon fasting and the implication for cancer. Curr. Opin. Oncol. 2013, 25, 630–636. [Google Scholar] [CrossRef] [Green Version]
- Colak, Y.; Ozturk, O.; Senates, E.; Tuncer, I.; Yorulmaz, E.; Adali, G.; Doganay, L.; Enc, F.Y. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med. Sci. Monit. 2011, 17, HY5–HY9. [Google Scholar] [CrossRef] [Green Version]
- Luci, C.; Bourinet, M.; Leclère, P.S.; Anty, R.; Gual, P. Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies. Front. Endocrinol. 2020, 11, 597648. [Google Scholar] [CrossRef] [PubMed]
- de Gregorio, E.; Colell, A.; Morales, A.; Marí, M. Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease. Int. J. Mol. Sci. 2020, 21, 3858. [Google Scholar] [CrossRef] [PubMed]
- Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007, 450, 712–716. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nassir, F.; Ibdah, J.A. Sirtuins and nonalcoholic fatty liver disease. World J. Gastroenterol. 2016, 22, 10084–10092. [Google Scholar] [CrossRef]
- Kundu, A.; Dey, P.; Park, J.H.; Kim, I.S.; Kwack, S.J.; Kim, H.S. EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats. Cells 2020, 9, 1101. [Google Scholar] [CrossRef]
Composition | Liver-Related Effects | ||||||
---|---|---|---|---|---|---|---|
Cytolysis | Steatosis | HCB | Inflammation | Fibrosis | Cholestasis | References | |
Bifidobacterium longum | + | + | ± | ± | [168] | ||
Lactobacillus acidophilus | + | [178] | |||||
L. acidophilus, B. lactis | + | [170] | |||||
L. rhamnosus | + | [169] | |||||
L. plantarum * | + | [179] | |||||
L. paracasei * | + | + | [180] | ||||
L. johnsonii * | + | + | [181] | ||||
L. reuteri | + | [182] | |||||
L. delbrueckii subsp. bulgaricus, Streptococcus thermophilus | + | [183] | |||||
L. acidophilus, L. rhamnosus, B. bifidum, B. lactis | + | + | [184] | ||||
L. acidophilus, L. rhamnosus, L. plantarum, L. delbrueckii subsp. bulgaricus, B. bifidum | + | + | [185] | ||||
L. acidophilus, L. rhamnosus, L. paracasei, B. lactis, B. breve, Pediococcus pentosaceus | + | [172] | |||||
L. acidophilus, L. plantarum, L. paracasei, L. delbrueckii subsp. bulgaricus, B. breve, B. longum, B. infantis | ± | [171] | |||||
Lactobacillus spp., Bifidobacterium spp., Lactococcus spp., Propionibacterium spp., Acetobacter spp. | + | + | ± | + | [173] | ||
L. acidophilus, L. plantarum, L. delbrueckii subsp. bulgaricus, L. casei, B. breve, B. longum, B. infantis, S. thermophilus | + | [186] | |||||
Clostridium butyricum * | + | + | [177] | ||||
Saccharomyces boulardii * | + | + | [176] |
Name | Mechanism of Action | Development Phase | Liver-Related Effects | ||||||
---|---|---|---|---|---|---|---|---|---|
Cytolysis | Steatosis | HCB | Inflammation | Fibrosis | Cholestasis | References | |||
Resmetirom | THRβ agonist | 3 | + | + | ± | ± | + | + | [11] |
VK2809 | THRβ agonist | 2 | + | [12] | |||||
ASC41 * | THRβ agonist | 2 | + | + | + | + | [13] | ||
TERN-501 * | THRβ agonist | 1 | + | + | + | [15] | |||
Firsocostat ** | ACC inhibitor | 2 | + | + | + | + | + | ± | [23] |
Clesacostat ** | ACC inhibitor | 2 | + | [24,31] | |||||
ASC40 | FASN inhibitor | 2 | + | + | + | + | [16] | ||
Aramchol | SCD1 inhibitor | 3 | + | + | + | + | + | [30] | |
Ervogastat | DGAT2 inhibitor | 2 | + | [31] | |||||
ION224 | DGAT2 inhibitor | 1 | + | ± | [216] | ||||
Docosahexaenoic acid | ω-3 PUFA | - | + | [40] | |||||
Epeleuton | ω-3 PUFA | 2 | ± | [44] | |||||
Icosabutate | ω-3 PUFA | 2 | + | + | ± | + | [46] | ||
Eicosapentanoic acid * | ω-3 PUFA | - | + | + | + | [218] | |||
Obeticholic acid | FXR agonist | 3 | + | + | + | + | + | + | [49,50] |
EDP-305 | FXR agonist | 2 | + | + | + | + | [54,56] | ||
Tropifexor | FXR agonist | 2 | + | + | + | + | [63] | ||
Cilofexor | FXR agonist | 2 | + | + | + | [64] | |||
Vonafexor | FXR agonist | 2 | + | + | + | [65] | |||
MET409 | FXR agonist | 2 | + | + | [59] | ||||
TERN-101 | FXR agonist | 2 | + | + | [67] | ||||
ASC42 * | FXR agonist | 2 | + | + | + | [16] | |||
INT-767 * | FXR agonist | 2 | + | + | + | + | [58] | ||
EDP-297 * | FXR agonist | 1 | + | + | + | ± | [219] | ||
BAR502 * | FXR agonist | - | + | + | + | [57] | |||
GW4064 * | FXR agonist | - | + | + | [220] | ||||
Aldafermin | FGF19 analogue | 2 | + | + | + | [70] | |||
Efruxifermin | FGF21 analogue | 2 | + | + | ± | + | + | [71] | |
BIO89-100 | FGF21 analogue | 2 | + | + | [72] | ||||
BFKB8488A | FGFR1c/KLB agonist | 2 | + | [74] | |||||
MK-3655 | FGFR1c/KLB agonist | 2 | + | [221] | |||||
GLP-1-Fc-FGF21 D1 * | FGF21 analogue, GLP1R agonist | - | + | + | [75] | ||||
GB1211 * | galectin-3 antagonist | 2 | + | [88] | |||||
GM-CT-01 * | galectin-3/1 antagonist | - | + | + | + | + | [79] | ||
JKB-122 | TLR4 antagonist | 2 | + | + | [83] | ||||
Eritoran * | TLR4 antagonist | - | + | + | + | [81] | |||
PXS-5153A * | LOXL2/3 inhibitor | - | + | + | [87] | ||||
Bezafibrate * | PPARα agonist | - | + | + | ± | [98] | |||
Pemafibrate | PPARα agonist | - | + | ± | + | [97] | |||
Fenofibrate | PPARα agonist | - | + | ± | + | [93,94] | |||
Gemfibrozil | PPARα agonist | + | [95] | ||||||
Nifedipine * | PPARγ agonist | - | + | + | [101] | ||||
Seladelpar | PPARδ agonist | 2 | + | + | [103] | ||||
Saroglitazar | PPARα/γ agonist | 2 | + | + | + | + | [104,105] | ||
Lanifibranor | PPARα/γ/δ agonist | 3 | + | + | + | + | + | [106] | |
Pioglitazone | PPARγ agonist, MPC inhibitor | - | + | + | + | + | [222] | ||
Lobeglitazone | PPARγ agonist, MPC inhibitor | - | + | + | [100] | ||||
Azemiglitazone | MPC inhibitor | 3 | + | ± | ± | ± | [107] | ||
PXL065 * | MPC inhibitor | 2 | + | + | + | [109] | |||
Semaglutide | GLP1R agonist | 3 | + | + | [113] | ||||
Exenatide | GLP1R agonist | - | + | + | + | [115,116] | |||
Lixisenatide | GLP1R agonist | - | + | + | + | [119] | |||
Liraglutide | GLP1R agonist | - | + | + | + | + | + | [120] | |
Dulaglutide | GLP1R agonist | - | + | + | + | [117,118] | |||
Teduglutide * | GLP2R agonist | - | + | ± | ± | [113] | |||
Tirzepatide | GLP1R/GIPR agonist | 2 | + | + | [123,124] | ||||
Cotadutide | GLP1R/GCGR agonist | 2 | + | + | ± | [127] | |||
Efinopegdutide * | GLP1R/GCGR agonist | 2 | + | ± | ± | [128] | |||
Pemvidutide | GLP1R/GCGR agonist | 1 | [223] | ||||||
HM15211 * | GLP1R/GCGR/GIPR agonist | 2 | + | + | [131] | ||||
Sitagliptin | DPP4 inhibitor | - | + | + | ± | [134] | |||
Vildagliptin | DPP4 inhibitor | - | + | + | + | [135] | |||
Saxagliptin | DPP4 inhibitor | - | + | + | ± | + | [136] | ||
Alogliptin | DPP4 inhibitor | - | + | [139] | |||||
Omarigliptin | DPP4 inhibitor | - | + | + | + | + | + | [137] | |
Teneligliptin | DPP4 inhibitor | - | + | + | [138] | ||||
Evogliptin * | DPP4 inhibitor | - | + | + | + | [141] | |||
Anagliptin * | DPP4 inhibitor | - | + | + | + | [142,143] | |||
Trelagliptin * | DPP4 inhibitor | - | + | + | + | ± | [144] | ||
Gemigliptin * | DPP4 inhibitor | - | + | + | + | [145] | |||
Linagliptin * | DPP4 inhibitor | - | + | + | [146] | ||||
Dapagliflozin | SGLT2 inhibitor | - | + | + | ± | + | [150,224] | ||
Empagliflozin | SGLT2 inhibitor | - | + | + | + | + | + | [151,225] | |
Canagliflozin | SGLT2 inhibitor | - | + | + | + | + | [152] | ||
Ipragliflozin | SGLT2 inhibitor | - | ± | + | + | [154,226] | |||
Ertugliflozin | SGLT2 inhibitor | - | + | [156] | |||||
Remogliflozin | SGLT2 inhibitor | - | + | + | [155] | ||||
Luseogliflozin | SGLT2 inhibitor | - | + | + | + | [157,158] | |||
Tofogliflozin | SGLT2 inhibitor | - | + | + | + | + | [159] | ||
Licogliflozin ** | SGLT1/2 inhibitor | 2 | + | + | + | [160,161] | |||
SGL5213 * | iSGLT1 inhibitor | - | + | + | ± | + | [162] | ||
Miglitol | α-glucosidase inhibitor | - | + | + | ± | + | + | [165] | |
Acarbose | α-glucosidase inhibitor | - | + | [164] | |||||
Voglibose * | α-glucosidase inhibitor | - | + | [166] | |||||
Liver-derived MSC | MSC | 2 | + | + | [192] | ||||
Umbilical cord-derived MSC * | MSC | - | + | [188] | |||||
Compact bone-derived MSC * | MSC | - | + | + | + | + | [189] | ||
Tesamorelin | GHRH analogue | 3 | + | + | [196] | ||||
Berberine ursodeoxycholate | multimodal metabolic | 2/1 | + | + | + | [202] | |||
Miricorilant | GR agonist/antagonist, MR antagonist | 2 | + | [203] | |||||
Nitazoxanide * | AMPK activator | 2 | + | + | [204,205] | ||||
PXL770 | AMPK activator | 2 | + | [227] | |||||
Leucine + metformin + sildenafil | AMPK activator, eNOS activator | 2 | + | [228] | |||||
Pirfenidone * | multimodal antifibrotic | - | + | + | [209] | ||||
PBI-4547 * | GPCR84 antagonist | - | + | + | ± | [229] | |||
CpdA * | GPCR84 antagonist | - | + | + | + | + | [230] | ||
CpdB * | GPCR84 antagonist | - | + | + | + | + | [230] | ||
GPR120 agonist III * | GPCR120 agonist | - | + | ± | + | [231] | |||
Metabolitin * | GPRC6A agonist | - | + | + | + | [232] | |||
SCO-267 * | GPR40 agonist | - | + | + | + | [233] | |||
Evolocumab | PCSK9 inhibitor | - | ± | [234] | |||||
Alirocumab | PCSK9 inhibitor | - | ± | [234] | |||||
X203 * | IL11 antagonist | - | + | + | + | + | [212] | ||
X209 * | IL11RA antagonist | - | [212] | ||||||
Ezetimibe | NPC1L1 inhibitor | - | + | ± | + | [235] | |||
ORMD-0801 | oral insulin | 2 | + | [236] | |||||
GalNAc-Stk25 ASO * | anti-STK25 ASO | - | + | + | + | + | [237] | ||
Tipelukast * | LTR antagonist, PDE3/4 inhibitor, 5-LO/LT inhibitor | 2 | ± | + | + | + | [210] | ||
CM-101 * | CCL24 antagonist | 2 | + | ± | ± | ± | + | ± | [238] |
Namodenoson | A3AR agonist | 2 | + | [214,239] | |||||
PLN-1474 * | αvβ1 antagonist | 1 | + | [240] | |||||
CB4211 | MOTS-c analogue | 1 | + | + | [241] | ||||
CER-209 * | P2Y13R agonist | 1 | + | + | [242] | ||||
DUR-928 | multitarget epigenetic regulator | 2 | + | + | + | + | [217] | ||
CRV431 | cyclophilin A/B/D inhibitor | 2 | + | [243] | |||||
LPCN 1144 | androgen receptor agonist | 2 | + | + | + | + | [244] | ||
Osteocalcin * | N/A | - | + | + | + | + | [245] |
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Prikhodko, V.A.; Bezborodkina, N.N.; Okovityi, S.V. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022, 10, 274. https://doi.org/10.3390/biomedicines10020274
Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines. 2022; 10(2):274. https://doi.org/10.3390/biomedicines10020274
Chicago/Turabian StylePrikhodko, Veronika A., Natalia N. Bezborodkina, and Sergey V. Okovityi. 2022. "Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates" Biomedicines 10, no. 2: 274. https://doi.org/10.3390/biomedicines10020274
APA StylePrikhodko, V. A., Bezborodkina, N. N., & Okovityi, S. V. (2022). Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines, 10(2), 274. https://doi.org/10.3390/biomedicines10020274