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A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice.

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is emerging as a major public health issue and is associated with significant liver-related morbidity and mortality. At present, there are no approved drug therapies for NASH. The transcriptional coactivator with PDZ-binding motif (TAZ; encoded by WW domain-containing transcription regulator 1 [WWTR1]) is up-regulated in hepatocytes in NASH liver from humans and has been shown to causally promote inflammation and fibrosis in mouse models of NASH. As a preclinical test of targeting hepatocyte TAZ to treat NASH, we injected stabilized TAZ small interfering RNA (siRNA) bearing the hepatocyte-specific ligand N-acetylgalactosamine (GalNAc-siTAZ) into mice with dietary-induced NASH. As a preventative regimen, GalNAc-siTAZ inhibited inflammation, hepatocellular injury, and the expression of profibrogenic mediators, accompanied by decreased progression from steatosis to NASH. When administered to mice with established NASH, GalNAc-siTAZ partially reversed hepatic inflammation, injury, and fibrosis. Conclusion: Hepatocyte-targeted siTAZ is potentially a novel and clinically feasible treatment for NASH.

SUBMITTER: Wang X

PROVIDER: S-EPMC6719739 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Wang Xiaobo X Sommerfeld Mark R MR Jahn-Hofmann Kerstin K Cai Bishuang B Filliol Aveline A Remotti Helen E HE Schwabe Robert F RF Kannt Aimo A Tabas Ira I

Hepatology communications 20190723 9

Nonalcoholic steatohepatitis (NASH) is emerging as a major public health issue and is associated with significant liver-related morbidity and mortality. At present, there are no approved drug therapies for NASH. The transcriptional coactivator with PDZ-binding motif (TAZ; encoded by WW domain-containing transcription regulator 1 [<i>WWTR1</i>]) is up-regulated in hepatocytes in NASH liver from humans and has been shown to causally promote inflammation and fibrosis in mouse models of NASH. As a p ...[more]

PMID: 31497743

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Project description:The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine-glycine-aspartic acid tripeptide (RGD)-binding, integrin antagonist (3S)-3-(3-bromo-5-(tert-butyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]-12). We hypothesized that RGD-binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM-12 in a choline deficient, amino-acid defined, high-fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM-12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM-12. Fibrosis measured by analysis of liver collagen was reduced by CWHM-12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM-12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD-binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.

Dataset Information

A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Publications

A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Similar Datasets

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