Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis

Sci Rep. 2016 Jun 21;6:28432. doi: 10.1038/srep28432.

Abstract

Interstitial fibrosis represents a key pathological process in non-alcoholic steatohepatitis (NASH). In the liver, fibrogenesis is primarily mediated by activated hepatic stellate cells (HSCs) transitioning from a quiescent state in response to a host of stimuli. The molecular mechanism underlying HSC activation is not completely understood. Here we report that there was a simultaneous up-regulation of PIAS4 expression and down-regulation of SIRT1 expression accompanying increased hepatic fibrogenesis in an MCD-diet induced mouse model of NASH. In cultured primary mouse HSCs, stimulation with high glucose activated PIAS4 while at the same time repressed SIRT1. Over-expression of PIAS4 directly repressed SIRT1 promoter activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HSCs treated with high glucose. Estrogen, a known NASH-protective hormone, antagonized HSC activation by targeting PIAS4. Lentivirus-mediated delivery of short hairpin RNA (shRNA) targeting PIAS4 in mice ameliorated MCD diet induced liver fibrosis by normalizing SIRT1 expression in vivo. PIAS4 promoted HSC activation in a SIRT1-dependent manner in vitro. Mechanistically, PIAS4 mediated SIRT1 repression led to SMAD3 hyperacetylation and enhanced SMAD3 binding to fibrogenic gene promoters. Taken together, our data suggest SIRT1 trans-repression by PIAS4 plays an important role in HSC activation and liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Estrogens / pharmacology
  • Glucose / pharmacology
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Male
  • Mice
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Protein Inhibitors of Activated STAT / antagonists & inhibitors
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Smad3 Protein / metabolism
  • Up-Regulation / drug effects

Substances

  • Estrogens
  • Protein Inhibitors of Activated STAT
  • RNA, Small Interfering
  • Smad3 Protein
  • Sirtuin 1
  • Glucose