Hepatocyte-specific TAZ deletion downregulates p62/ Sqstm1 expression in nonalcoholic steatohepatitis

Biochem Biophys Res Commun. 2021 Jan 8:535:60-65. doi: 10.1016/j.bbrc.2020.12.038. Epub 2020 Dec 17.

Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by inflammation, hepatocellular injury, and different degrees of fibrosis. Previous studies have indicated that the transcriptional coactivator with PDZ-binding motif TAZ (WWTR1) is correlated with the increased level of liver cholesterol which suppresses TAZ proteasomal degradation and promotes fibrotic NASH by activating soluble adenylyl cyclase -calcium-RhoA pathway. However, the exact mechanism by which TAZ promotes inflammatory and hepatocyte injury has not yet been fully addressed. Reportedly, p62/Sqstm1plays a pivotal role in inflammatory and hepatocyte injury during NASH development. Here, we demonstrated that p62/Sqstm1 was overexpressed in the livers of mouse NASH models in a TAZ-dependent manner. In addition, hepatocyte-specific TAZ deletion reduced p62/Sqstm1 both in vitro and in vivo. Strikingly, luciferase reporter data demonstrated that p62/Sqstm1 is a TAZ/TEAD target gene and can be transcriptionally regulated by TAZ, indicating that hepatocyte-specific TAZ deletion downregulates p62/Sqstm1 expression in NASH.

Keywords: Nonalcoholic steatohepatitis; TAZ /WWTR1; p62 /SQSTM1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Line
  • Diet
  • Down-Regulation*
  • Gene Deletion*
  • Gene Silencing
  • Hepatocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Organ Specificity*
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism*
  • Trans-Activators / metabolism*
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • Sequestosome-1 Protein
  • Trans-Activators
  • Wwtr1 protein, mouse