RXRα Ligand CP2 Inhibits Nonalcoholic Fatty Liver Via AMPK Signaling Axis

Background and objective:Nonalcoholic steatohepatitis(NASH)is becoming the main stimulus promoting chronic liver metabolic diseases.Nuclear receptors are thought to be a promising drug target for the treatment of NASH,and some compounds targeting the peroxisome proliferator activated receptors(PPARs),the liver X receptor(LXR)and the farnesoid X receptor(FXR)have shown therapeutic effects in clinical trials.Retinoid X receptor alpha(RXRα)is one of the most important members of the nuclear receptor family.It is still unclear whether RXRa can be targeted for the treatment of NASH.Methods:Therapeutic effects of nuclear receptor RXRa ligand CP2 were verified by two NASH mouse models,and its mechanisms were demonstrated in vitro with HepG2 model induced by palmitic acid(PA)and oleic acid(OA).Results:The NASH mouse model demonstrated that CP2 could reduce liver weight and triglyceride accumulation,improve liver steatosis and ameliorate ALT and AST levels in serum.Further,CP2 also inhibited liver fibrosis,and it showed better therapeutic effects comparing to the positive control drug OCA.These results showed that compound CP2 had effective therapeutic effects on NASH.PA and OA were used to induce lipid accumulation in cell model in vitro.CP2 decreased triglyceride level and lipid deposition in a RXRα/AMPK/ACC-dependent manner in HepG2 and primary hepatocytes.Conclusion:CP2,the small molecular ligand of RXRα,significantly improves liver pathological indexes via activating AMPK signal pathway in RXRa dependent manner,and this effect is better than that of OCA.Therefore,CP2 is expected to become a promising compound for NASH treatment.