LAUSR

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, that has no specific pharmacological treatments partially due to the unclear pathophysiological mechanisms. Regulators of G protein signaling (RGS) proteins are proteins that negatively regulate G protein-coupled receptor (GPCR) signaling. The member of R4/B subfamily are the smallest RGS proteins in size and RGS5 belongs to this family, which mediates pluripotent biological functions via canonical G-protein mediated pathways and non-GPCR pathways. Here, we combined genetic engineering rodent model and transcriptomics sequencing approach to investigate the role and regulatory mechanism of RGS5 in the development of NAFLD. APPROACH & RESULTS In this study, we found that RGS5 protects against NAFLD and NASH. Using RNA sequencing and an unbiased systematic investigative approach, we found that the activation of MAPK signaling cascades in response to metabolic challenge is negatively associated with hepatic RGS5 expression. Mechanistically, we found that the 64-181aa fragment of RGS5 directly interacts with TGF-β-activated kinase 1 (TAK1) via the 1 -300aa fragment and inhibits TAK1 phosphorylation and the subsequent JNK/p38 pathways activation. CONCLUSION 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.