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

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.