Mechanisms Of Regulator Of G Protein Signaling 5(RGS5) In The Development Of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease(NAFLD)is the most prevalent chronic liver disease affecting over 1.7 billion people,but without a pharmacological treatment.The spectrum of NAFLD includes simple steatosis and nonalcoholic steatohepatitis(NASH),the latter of which put subjects at high risks of cirrhosis and HCC.As estimated,the drug market of NAFLD/NASH would be $20 to $35 billion per year by 2025.However,the complexity and heterogeneity of NAFLD pathogenesis hampered the exploring therapeutic targets and developing pharmacological interventions.Regulators of G protein signaling(RGS)protein negatively regulate G protein-coupled receptor(GPCR)signaling.RGS5 is a member of the R4/B subfamily of the RGS protein family and mediates pluripotent biological functions via both GPCR-dependent and independent pathways.However,the function of RGS5 on NAFLD progression is largely unknown.In this study,we found that the expression of RGS5 protein in liver tissues of NASH patients was significantly down-regulated compared with normal liver tissues.Consistent with the results of clinical samples,feeding a high-fat diet(HFD)significantly decreased the protein expression of RGS5 in mouse liver.Based on RGS5overexpressing hepatocytes,we demonstrated that RGS5 attenuates palmitic acid and oil acid(PO)-induced lipid accumulation and the subsequent inflammatory response.We further constructed hepatocyte-specific Rgs5-knockout(Rgs5-CKO)mice and subjected them to HFD feeding in parallel with their littermate controls.Consequently,hepatocellular specific RGS5 gene knockout exacerbated the metabolic syndrome of liver lipid degeneration,chronic inflammation and insulin resistance induced by HFD and HFHC,and leading to aggravated development of NAFLD.To investigate the molecular mechanism underlying RGS5 function,we performed RNA sequencing and an unbiased systematic biology investigative approach,with the results that RGS5 robustly blocked the activation of MAPK signaling cascades.Mechanistically,the RGS domain(64-181aa)of RGS5 directly interacts with TGF-βactivated kinase 1(TAK1)via the 1-300aa fragment to inhibit TAK1 phosphorylation and the subsequent JNK/p38 activation,and thus improves the development of dietinduced NAFLD progression.To further confirm that RGS5 was dependent on TAK1 to inhibit the development of NAFLD,we applied the TAK1 inhibitor((5Z)-7oxozeaeno,5Z-7-OX)at the primary hepatocyte level and individual level of Rgs5-flox and Rgs5-cko mice,the study found that TAK1 catalytic activity inhibitor(5-7-Z-OX)significantly blocked HFD-induced TAK1-JNK/p38 signaling amplification in Rgs5CKO mouse livers,Furthermore,inhibition of TAK1 activation rescues the RGS5 deletion-induced exacerbation of NAFLD.In conclusion,we found that in vivo and in vitro high-fat models,hepatocellular specific RGS5 deficiency exacerbates the development of NAFLD induced by high-fat models.RGS5 directly binds to TAK1,preventing its hyperphosphorylation and the activation of the downstream JNK/p38 signaling cascade.RGS5 depends on the activity of regulating TAK1 to inhibit the occurrence and development of NAFLD induced by high-fat diet.Thus,RGS5 might represent a potential drug design target molecule for fine-tuning the activity of TAK1 and for the prevention/treatment of NAFLD.