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Current Hepatology Reports

Erschienen in:

05.08.2020 | Fatty Liver Disease (V Ajmera, Section Editor)

Metabolic Targets in Nonalcoholic Steatohepatitis: Treating the Disease at the Metabolic Root

verfasst von: Pankaj Aggarwal, Tamneet Singh, Naim Alkhouri

Erschienen in: Current Hepatology Reports | Ausgabe 3/2020

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Abstract

Purpose of Review

Nonalcoholic fatty liver disease (NAFLD) and its more aggressive form nonalcoholic steatohepatitis (NASH) are a leading cause of chronic liver disease worldwide. Thus far, there are no FDA-approved therapeutic options for NASH. This review discusses relevant and recent findings in the development of pharmacotherapy that targets the metabolic processes implicated in NASH.

Recent Findings

Several key drugs have been identified across various drug classes. Among inhibitors of de novo lipogenesis, the SCD-1 inhibitor aramchol and the ACC inhibitor firsocostat are the most advanced. Within nuclear hormone receptor agonists, PPARα/δ agonist elafibranor and PPARα/γ agonist saroglitazar show promise with respect to improvement in NASH histology and hepatic steatosis. Additionally, THR-β agonist resmetirom showed significant reduction in hepatic steatosis and NASH resolution. Larger studies with longer treatment duration are needed to establish safety and efficacy of these metabolic drugs.

Summary

Significant progress has been made over the past decade in testing drugs that modulate the metabolic targets responsible for NASH progression.

Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, et al. NASH leading cause of liver transplant in women: Updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol. 2018;113:1649–59. https://doi.org/10.1038/s41395-018-0088-6.CrossRefPubMedPubMedCentral

Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016;65:1017–25. https://doi.org/10.1016/j.metabol.2016.01.012.CrossRefPubMed

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;64:73–84. https://doi.org/10.1002/hep.28431.CrossRefPubMed

Esler WP, Bence KK. Metabolic targets in nonalcoholic fatty liver disease. Cell Mol Gastroenterol Hepatol. 2019;8:247–67.CrossRefPubMedPubMedCentral

Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings. Hepatology. 2011;53:810–20. https://doi.org/10.1002/hep.24127.CrossRefPubMed

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the american association for the study of liver diseases. Hepatology. 2018;67:328–57. https://doi.org/10.1002/hep.29367.CrossRefPubMed

Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48. https://doi.org/10.1016/j.metabol.2015.12.012.CrossRefPubMed

Kitade H, Chen G, Ni Y, Ota T. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients. 2017;9. https://doi.org/10.3390/nu9040387.

Jung UJ, Choi MS. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15:6184–223. https://doi.org/10.3390/ijms15046184.CrossRefPubMedPubMedCentral

10.

Manne V, Handa P, Kowdley KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22:23–37.PubMed

11.

Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. https://doi.org/10.1002/cphy.c170012.CrossRefPubMedPubMedCentral

12.

Caligiuri A, Gentilini A, Marra F. Molecular pathogenesis of NASH. Int J Mol Sci. 2016;17. https://doi.org/10.3390/ijms17091575.

13.

Kreuz S, Schoelch C, Thomas L, Rist W, Rippmann JF, Neubauer H. Acetyl-CoA carboxylases 1 and 2 show distinct expression patterns in rats and humans and alterations in obesity and diabetes. Diabetes Metab Res Rev. 2009;25:577–86. https://doi.org/10.1002/dmrr.997.CrossRefPubMed

14.

Chen L, Duan Y, Wei H, Ning H, Bi C, Zhao Y, et al. Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors. Expert Opin Investig Drugs. 2019;28:917–30. https://doi.org/10.1080/13543784.2019.1657825.CrossRefPubMed

15.

Harwood HJ, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 2003;278:37099–111. https://doi.org/10.1074/jbc.M304481200.CrossRefPubMed

16.

Griffith DA, Kung DW, Esler WP, Amor PA, Bagley SW, Beysen C, et al. Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes. J Med Chem. 2014;57:10512–26. https://doi.org/10.1021/jm5016022.CrossRefPubMedPubMedCentral

17.

Kim CW, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: A bedside to bench investigation. Cell Metab. 2017;26:394–406.e6.PubMedPubMedCentral

18.

Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, et al. Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology. 2018;68:2197–211. https://doi.org/10.1002/hep.30097.CrossRefPubMed

19.

Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA carboxylase inhibitor (PF-05221304): A three-part randomized phase 1 study. Clin Pharmacol Drug Dev. 2020. https://doi.org/10.1002/cpdd.782.

20.

Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2018;16:1983–1991.e3.PubMed

21.

• Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155:1463–73. https://doi.org/10.1053/j.gastro.2018.07.027Largest study to date demonstrating efficacy of firsocostat in humans with NASH.CrossRefPubMed

22.

Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. GS-0976 (firsocostat): An investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:135–41. https://doi.org/10.1080/13543784.2020.1668374.CrossRefPubMed

23.

Jones SF, Infante JR. Molecular pathways: Fatty acid synthase. Clin Cancer Res. 2015;21:5434–8. https://doi.org/10.1158/1078-0432.CCR-15-0126.CrossRefPubMed

24.

Huang C, Freter C. Lipid metabolism, apoptosis and cancer therapy. Int J Mol Sci. 2015;16:924–49. https://doi.org/10.3390/ijms16010924.CrossRefPubMedPubMedCentral

25.

Syed-Abdul MM, Parks EJ, Gaballah AH, Bingham K, Hammoud GM, Kemble G, et al. First-in-class fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology. 2019. https://doi.org/10.1002/hep.31000.

26.

Clinical trials. clinicaltrials.gov. Accessed March 26, 2020.

27.

Koeberle A, Loser K, Thurmer M. Stearoyl-CoA desaturase-1 and adaptive stress signaling. Biochim Biophys Acta. 1861;2016:1719–26.

28.

Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085–91.e1. https://doi.org/10.1016/j.cgh.2014.04.038.CrossRefPubMed

29.

•• Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. One-year results of the global phase 2b randomized placebo- controlled ARREST trial of aramchol, a stearoyl CoA desaturase modulator in NASH patients. Hepatology. 2018; This ARREST trial demonstrates the efficacy of aramchol in treating NASH as treatment was associated with resolution of NASH and improvement in fibrosis.

30.

Nehemya G. Galmed pharmaceuticals initiated ARMOR, a phase 3/4 registrational study of aramchol in subjects with NASH and fibrosis. http://galmedpharma.investorroom.com/2019-09-26-Galmed-Pharmaceuticals-Initiated-ARMOR-a-Phase-3-4-Registrational-Study-of-Aramchol-in-Subjects-With-NASH-and-Fibrosis. Updated 2019.

31.

Yang M, Nickels JT. MOGAT2: A new therapeutic target for metabolic syndrome. Diseases. 2015;3:176–92. https://doi.org/10.3390/diseases3030176.CrossRefPubMedPubMedCentral

32.

Devasthale P, Cheng D. Monoacylglycerol acyltransferase 2 (MGAT2) inhibitors for the treatment of metabolic diseases and nonalcoholic steatohepatitis (NASH). J Med Chem. 2018;61:9879–88. https://doi.org/10.1021/acs.jmedchem.8b00864.CrossRefPubMed

33.

Okuma C, Ohta T, Tadaki H, Ishigure T, Sakata S, Taniuchi H, et al. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis. J Pharmacol Sci. 2015;128:150–7. https://doi.org/10.1016/j.jphs.2015.06.007.CrossRefPubMed

34.

Bhatt-Wessel B, Jordan TW, Miller JH, Peng L. Role of DGAT enzymes in triacylglycerol metabolism. Arch Biochem Biophys. 2018;655:1–11.CrossRefPubMed

35.

Gluchowski NL, Gabriel KR, Chitraju C, Bronson RT, Mejhert N, Boland S, et al. Hepatocyte deletion of triglyceride-synthesis enzyme acyl CoA: Diacylglycerol acyltransferase 2 reduces steatosis without increasing inflammation or fibrosis in mice. Hepatology. 2019;70:1972–85. https://doi.org/10.1002/hep.30765.CrossRefPubMed

36.

Amin NB, Carvajal-Gonzalez S, Purkal J, Zhu T, Crowley C, Perez S, et al. Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis. Sci Transl Med. 2019;11:eaav9701. https://doi.org/10.1126/scitranslmed.aav9701.CrossRefPubMed

37.

Hong DJ, Jung SH, Kim J, Jung D, Ahn YG, Suh KH, et al. Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors. J Enzyme Inhib Med Chem. 2020;35:227–34. https://doi.org/10.1080/14756366.2019.1693555.CrossRefPubMed

38.

Okour M, Gress A, Zhu X, Rieman D, Lickliter JD, Brigandi RA. First-in-human pharmacokinetics and safety study of GSK3008356, a selective DGAT1 inhibitor, in healthy volunteers. Clin Pharmacol Drug Dev. 2019;8:1088–99. https://doi.org/10.1002/cpdd.691.CrossRefPubMed

39.

Okour M, Brigandi RA, Tenero D. A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal-induced triglyceride turnover in healthy subjects. Fundam Clin Pharmacol. 2019;33:567–80. https://doi.org/10.1111/fcp.12455.CrossRefPubMed

40.

Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocr Rev. 2018;39:760–802. https://doi.org/10.1210/er.2018-00064.CrossRefPubMed

41.

Marion-Letellier R, Savoye G, Ghosh S. Fatty acids, eicosanoids and PPAR gamma. Eur J Pharmacol. 2016;785:44–9.PubMed

42.

Chen J, Montagner A, Tan NS, Wahli W. Insights into the role of PPARbeta/delta in NAFLD. Int J Mol Sci. 2018;19. https://doi.org/10.3390/ijms19071893.

43.

Larter CZ, Yeh MM, Van Rooyen DM, Brooling J, Ghatora K, Farrell GC. Peroxisome proliferator-activated receptor-alpha agonist, wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2012;27:341–50. https://doi.org/10.1111/j.1440-1746.2011.06939.x.CrossRefPubMed

44.

Zhang N, Lu Y, Shen X, Bao Y, Cheng J, Chen L, et al. Fenofibrate treatment attenuated chronic endoplasmic reticulum stress in the liver of nonalcoholic fatty liver disease mice. Pharmacology. 2015;95:173–80. https://doi.org/10.1159/000380952.CrossRefPubMed

45.

Shiri-Sverdlov R, Wouters K, van Gorp PJ, Gijbels MJ, Noel B, Buffat L, et al. Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J Hepatol. 2006;44:732–41.CrossRefPubMed

46.

Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–7.CrossRefPubMed

47.

Fernandez-Miranda C, Perez-Carreras M, Colina F, Lopez-Alonso G, Vargas C, Solis-Herruzo JA. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2008;40:200–5. https://doi.org/10.1016/j.dld.2007.10.002.CrossRefPubMed

48.

Takei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, et al. Selective peroxisome proliferator-activated receptor-alpha modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-alpha pathway and improves lipid metabolism in mice. J Diabetes Investig. 2017;8:446–52. https://doi.org/10.1111/jdi.12621.CrossRefPubMedPubMedCentral

49.

Honda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017;7:42477. https://doi.org/10.1038/srep42477.CrossRefPubMedPubMedCentral

50.

Lee HJ, Yeon JE, Ko EJ, Yoon EL, Suh SJ, Kang K, et al. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease. World J Gastroenterol. 2015;21:12787–99. https://doi.org/10.3748/wjg.v21.i45.12787.CrossRefPubMedPubMedCentral

51.

Kostadinova R, Montagner A, Gouranton E, Fleury S, Guillou H, Dombrowicz D, et al. GW501516-activated PPARbeta/delta promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci. 2012;2:34. https://doi.org/10.1186/2045-3701-2-34.CrossRefPubMedPubMedCentral

52.

Shan W, Palkar PS, Murray IA, McDevitt EI, Kennett MJ, Kang BH, et al. Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol Sci. 2008;105:418–28. https://doi.org/10.1093/toxsci/kfn142.CrossRefPubMedPubMedCentral

53.

Silva AKS, Peixoto CA. Role of peroxisome proliferator-activated receptors in non-alcoholic fatty liver disease inflammation. Cell Mol Life Sci. 2018;75:2951–61. https://doi.org/10.1007/s00018-018-2838-4.CrossRefPubMed

54.

Hans Vitzthum. CymaBay therapeutics halts clinical development of seladelpar. https://ir.cymabay.com/press-releases/detail/476/cymabay-therapeutics-halts-clinical-development-of-seladelpar. Updated 2019.

55.

Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017;136:65–74.PubMed

56.

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85. https://doi.org/10.1056/NEJMoa0907929.CrossRefPubMedPubMedCentral

57.

Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16:558–566.e2. https://doi.org/10.1016/j.cgh.2017.12.001.CrossRefPubMed

58.

Yaghoubi M, Jafari S, Sajedi B, Gohari S, Akbarieh S, Heydari AH, et al. Comparison of fenofibrate and pioglitazone effects on patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2017;29:1385–8. https://doi.org/10.1097/MEG.0000000000000981.CrossRefPubMed

59.

Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial. Ann Intern Med. 2016;165:305–15. https://doi.org/10.7326/M15-1774.CrossRefPubMed

60.

Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis. JAMA Intern Med. 2017;177:633–40. https://doi.org/10.1001/jamainternmed.2016.9607.CrossRefPubMedPubMedCentral

61.

Cariou B, Hanf R, Lambert-Porcheron S, Zair Y, Sauvinet V, Noel B, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care. 2013;36:2923–30. https://doi.org/10.2337/dc12-2012.CrossRefPubMedPubMedCentral

62.

Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34:2008–14. https://doi.org/10.2337/dc11-0093.CrossRefPubMedPubMedCentral

63.

Colin S, Briand O, Touche V, Wouters K, Baron M, Pattou F, et al. Activation of intestinal peroxisome proliferator-activated receptor-alpha increases high-density lipoprotein production. Eur Heart J. 2013;34:2566–74. https://doi.org/10.1093/eurheartj/ehs227.CrossRefPubMed

64.

Tolbol KS, Stierstorfer B, Rippmann JF, Veidal SS, Rigbolt KTG, Schonberger T, et al. Disease progression and pharmacological intervention in a nutrient-deficient rat model of nonalcoholic steatohepatitis. Dig Dis Sci. 2019;64:1238–56. https://doi.org/10.1007/s10620-018-5395-7.CrossRefPubMed

65.

Briand F, Heymes C, Bonada L, Angles T, Charpentier J, Branchereau M, et al. A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death. Clin Transl Sci. 2020. https://doi.org/10.1111/cts.12735.

66.

Roth JD, Veidal SS, Fensholdt LKD, Rigbolt KTG, Papazyan R, Nielsen JC, et al. Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH. Sci Rep. 2019;9:9046. https://doi.org/10.1038/s41598-019-45178-z.CrossRefPubMedPubMedCentral

67.

Li TH, Yang YY, Huang CC, Liu CW, Tsai HC, Lin MW, et al. Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis. Clin Sci (Lond). 2019;133:531–44. https://doi.org/10.1042/CS20180873.CrossRef

68.

Tolbol KS, Kristiansen MN, Hansen HH, Veidal SS, Rigbolt KT, Gillum MP, et al. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol. 2018;24:179–94. https://doi.org/10.3748/wjg.v24.i2.179.CrossRefPubMedPubMedCentral

69.

•• Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–1159.e5. https://doi.org/10.1053/j.gastro.2016.01.038The GOLDEN-505 trial demonstrated the efficacy of elafibranor in improving NASH histology, though the study did not meet its primary endpoint of NASH resolution.CrossRefPubMed

70.

Eichenbaum N, Lavin H. GENFIT: Announces results from interim analysis of RESOLVE-IT phase 3 trial of elafibranor in adults with NASH and fibrosis. https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3. Updated 2020.

71.

Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, et al. Dual PPARalpha/gamma agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018;38:1084–94. https://doi.org/10.1111/liv.13634.CrossRefPubMed

72.

Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Kowdley K, et al. A phase 2, prospective, multicenter, double-blind, randomized study of saroglitazar magnesium 1 MG, 2 MG, or 4 MG versus placebo in patients with nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis (EVIDENCES IV). Hepatology. 2019;10.

73.

Nawrat A. Zydus’ saroglitazar becomes first NASH drug approved globally. https://www.pharmaceutical-technology.com/news/saroglitazar-nash-first/. Updated 2020.

74.

Boubia B, Poupardin O, Barth M, Binet J, Peralba P, Mounier L, et al. Design, synthesis, and evaluation of a novel series of indole sulfonamide peroxisome proliferator activated receptor (PPAR) alpha/gamma/delta triple activators: Discovery of lanifibranor, a new antifibrotic clinical candidate. J Med Chem. 2018;61:2246–65. https://doi.org/10.1021/acs.jmedchem.7b01285.CrossRefPubMed

75.

Sinha R, Yen PM. Cellular action of thyroid hormone. 2000 doi: NBK285568.

76.

Sinha RA, Bruinstroop E, Singh BK, Yen PM. Nonalcoholic fatty liver disease and hypercholesterolemia: Roles of thyroid hormones, metabolites, and agonists. Thyroid. 2019;29:1173–91. https://doi.org/10.1089/thy.2018.0664.CrossRefPubMed

77.

Zucchi R. Thyroid hormone analogues: An update. Thyroid. 2020. https://doi.org/10.1089/thy.2020.0071.

78.

Vatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, et al. Thyroid hormone receptor-beta agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab. 2013;305:89. https://doi.org/10.1152/ajpendo.00573.2012.CrossRef

79.

Cable EE, Finn PD, Stebbins JW, Hou J, Ito BR, van Poelje PD, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology. 2009;49:407–17. https://doi.org/10.1002/hep.22572.CrossRefPubMed

80.

Martagon AJ, Lin JZ, Cimini SL, Webb P, Phillips KJ. The amelioration of hepatic steatosis by thyroid hormone receptor agonists is insufficient to restore insulin sensitivity in ob/ob mice. PLoS One. 2015;10:e0122987. https://doi.org/10.1371/journal.pone.0122987.CrossRefPubMedPubMedCentral

81.

Perra A, Simbula G, Simbula M, Pibiri M, Kowalik MA, Sulas P, et al. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 2008;22:2981–9. https://doi.org/10.1096/fj.08-108464.CrossRefPubMed

82.

• Loomba R, Neutel J, Mohseni R, Bernard D, Severance R, Dao M, et al. LBP-20-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:e150–1. https://doi.org/10.1016/S0618-8278(19)30266-XThis study demonstrated the association between reduction in hepatic steatosis and treatment with resmetirom.

83.

Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012–24. https://doi.org/10.1016/S0140-6736(19)32517-6.CrossRefPubMed

84.

Zarei M, Pizarro-Delgado J, Barroso E, Palomer X, Vazquez-Carrera M. Targeting FGF21 for the treatment of nonalcoholic steatohepatitis. Trends Pharmacol Sci. 2020;41:199–208.PubMed

85.

Tucker B, Li H, Long X, Rye KA, Ong KL. Fibroblast growth factor 21 in non-alcoholic fatty liver disease. Metabolism. 2019;101:153994.PubMed

86.

Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Investig. 2010;40:887–92. https://doi.org/10.1111/j.1365-2362.2010.02338.x.CrossRef

87.

Wu G, Li H, Fang Q, Zhang J, Zhang M, Zhang L, et al. Complementary role of fibroblast growth factor 21 and cytokeratin 18 in monitoring the different stages of nonalcoholic fatty liver disease. Sci Rep. 2017;7:5095. https://doi.org/10.1038/s41598-017-05257-5.CrossRefPubMedPubMedCentral

88.

Yin J, Bao L, Chen R, Gao W, Gao X, Yao W. Enhanced expression and distinctive characterization of a long-acting FGF21 and its potential to alleviate nonalcoholic steatohepatitis. Biochimie. 2018;151:166–75.PubMed

89.

Lee JH, Kang YE, Chang JY, Park KC, Kim HW, Kim JT, et al. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am J Transl Res. 2016;8:4750–63.PubMedPubMedCentral

90.

Bao L, Yin J, Gao W, Wang Q, Yao W, Gao X. A long-acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-adiponectin-IL17A pathway. Br J Pharmacol. 2018;175:3379–93. https://doi.org/10.1111/bph.14383.CrossRefPubMedPubMedCentral

91.

• Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: Results from a randomized phase 2 study. Obesity (Silver Spring). 2019;27:41–9. https://doi.org/10.1002/oby.22344This study demonstrated the efficacy of pegbelfermin in the improvement of hepatic steatosis.CrossRef

92.

Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2019;392:2705–17.PubMed

93.

Hawley C. All AKR-001 dose groups met week 12 efficacy endpoints in NASH phase 2a BALANCED study. https://ir.akerotx.com/news-releases/news-release-details/all-akr-001-dose-groups-met-week-12-efficacy-endpoints-nash. Updated 2020.

94.

Rakipovski G, Rolin B, Nohr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE(−/−) and LDLr(−/−) mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3:844–57. https://doi.org/10.1016/j.jacbts.2018.09.004.CrossRefPubMedPubMedCentral

95.

Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, 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;387:679–90. https://doi.org/10.1016/S0140-6736(15)00803-X.CrossRefPubMed

96.

Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24:73–9. https://doi.org/10.1097/MED.0000000000000311.CrossRefPubMedPubMedCentral

97.

Seko Y, Nishikawa T, Umemura A, Yamaguchi K, Moriguchi M, Yasui K, et al. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1–3 fibrosis. Diabetes Metab Syndr Obes. 2018;11:835–43. https://doi.org/10.2147/DMSO.S184767.CrossRefPubMedPubMedCentral

98.

Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: A randomized controlled trial (E-LIFT trial). Diabetes Care. 2018;41:1801–8. https://doi.org/10.2337/dc18-0165.CrossRefPubMed

99.

Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2020;65:623–31. https://doi.org/10.1007/s10620-019-5477-1.CrossRefPubMed

100.

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;87:13–9. https://doi.org/10.1016/j.curtheres.2017.07.002.CrossRefPubMedPubMedCentral

Titel: Metabolic Targets in Nonalcoholic Steatohepatitis: Treating the Disease at the Metabolic Root
verfasst von: Pankaj Aggarwal
Tamneet Singh
Naim Alkhouri
Publikationsdatum: 05.08.2020
Verlag: Springer US
Erschienen in: Current Hepatology Reports / Ausgabe 3/2020
Elektronische ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-020-00533-x

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