Hepatic Regulator of G Protein Signaling 5 Ameliorates Nonalcoholic Fatty Liver Disease by Suppressing Transforming Growth Factor Beta-Activated Kinase 1-c-Jun-N-Terminal Kinase/p38 Signaling

Hepatology. 2021 Jan;73(1):104-125. doi: 10.1002/hep.31242. Epub 2020 Nov 7.

Abstract

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, which has no specific pharmacological treatments partially because of the unclear pathophysiological mechanisms. Regulator of G protein signaling (RGSs) proteins are proteins that negatively regulate G protein-coupled receptor (GPCR) signaling. The members of the R4/B subfamily are the smallest RGS proteins in size, and RGS5 belongs to this family, which mediates pluripotent biological functions through canonical G protein-mediated pathways and non-GPCR pathways. This study combined a genetically engineered rodent model and a transcriptomics-sequencing approach to investigate the role and regulatory mechanism of RGS5 in the development of NAFLD.

Approach and results: This study found that RGS5 protects against NAFLD and nonalcoholic steatohepatitis. Using RNA sequencing and an unbiased systematic investigative approach, this study found that the activation of mitogen-activated protein kinase signaling cascades in response to metabolic challenge is negatively associated with hepatic RGS5 expression. Mechanistically, we found that the 64-181 amino-acid-sequence (aa) fragment of RGS5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) through the 1-300aa fragment and inhibits TAK1 phosphorylation and the subsequent c-Jun-N-terminal kinase (JNK)/p38 pathway activation.

Conclusions: In hepatocytes, RGS5 is an essential molecule that protects against the progression of NAFLD. RGS5 directly binds to TAK1, preventing its hyperphosphorylation and the activation of the downstream JNK/p38 signaling cascade. RGS5 is a promising target molecule for fine-tuning the activity of TAK1 and for the treatment of NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Insulin Resistance
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Liver / pathology*
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • RGS Proteins / metabolism*
  • Signal Transduction*

Substances

  • RGS Proteins
  • RGS5 protein, human
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7