A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice.
Hepatol Commun
; 3(9): 1221-1234, 2019 Sep.
Article
em En
| MEDLINE
| ID: mdl-31497743
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Hepatol Commun
Ano de publicação:
2019
Tipo de documento:
Article