Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis

Cell Metab. 2016 Dec 13;24(6):848-862. doi: 10.1016/j.cmet.2016.09.016. Epub 2016 Oct 27.

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Base Sequence
  • Cell Death
  • Diet
  • Disease Models, Animal
  • Disease Progression
  • Gene Silencing
  • Hedgehog Proteins / metabolism
  • Hepatic Stellate Cells / metabolism
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver / metabolism
  • Liver Cirrhosis / complications*
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Male
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / complications*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Trans-Activators
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • Wwtr1 protein, mouse