Role of the SRC-3 Inhibitor in Regulating the PPARα-LXRα-ABCA1 Pathway to Ameliorate Hepatic Lipid Metabolism in Diabetic Mice

LI Chunyan; XU Meihua; WANG Peng

doi:10.3639/j.issn.2095-3097.2025.09.027

Abstract：Objective To investigate the effects and mechanisms of the steroid receptor coactivator 3(SRC-3)inhibitor SRC-3-IN-1 on hepatic lipid metabolism disorders in diabetic mice.Methods Thirty-six C57BL/6 mice with diabetes induced by a high-fat diet combined with streptozotocin were divided into a model group,a 10 mg/kg SRC-3-IN-1 group,and a 20 mg/kg SRC-3-IN-1 group,with 12 mice per group.Twelve mice fed a standard diet were designated as the normal group,and the remaining groups continued to be fed a high-fat diet.The SRC-3-IN-1 groups received intraperitoneal injections of 10 mg/kg or 20 mg/kg SRC-3-IN-1,while the normal and model groups received 0.5%sodium carboxymethyl cellulose(vehicle).The treatment lasted 8 weeks,and the injection volume was adjusted weekly based on body weight.Assay kits were used to measure fasting blood glucose(FBG),serum total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).Hepatic morphology was observed using hematoxylin-eosin(H&E)staining,and lipid deposition was assessed by Oil Red O staining.Western blot was performed to detect the expression levels of SRC-3,key lipid synthesis proteins including sterol regulatory element-binding protein 1c(SREBP-1c)and acetyl-CoA carboxylase α(ACCα),as well as key lipid catabolism and oxidation proteins including peroxisome proliferator-activated receptor α(PPARα),liver X receptor α(LXRα),ATP-binding cassette transporter A1(ABCA1),and the PPARα downstream targets carnitine palmitoyltransferase 1A(CPT1A)and acyl-CoA oxidase 1(ACOX1).Co-immunoprecipitation(Co-IP)was used to validate the interaction between SRC-3 and PPARα in liver tissues.Results Compared with the normal group,the model group showed increased FBG,liver index,TC,TG,and LDL-C levels;decreased body weight and HDL-C levels;elevated ALT and AST levels;significant lipid deposition;upregulation of SRC-3,SREBP-1c,and ACCα expression;and downregulation of PPARα,LXRα,ABCA1,CPT1A,and ACOX1 expression(P<0.01).Compared with the model group,the SRC-3-IN-1 groups showed no significant changes in body weight or FBG,but exhibited a reduced liver index,alleviated lipid deposition,unaffected SREBP-1c and ACCα expression,restored activity of the PPARα-LXRα-ABCA1 lipid catabolism and oxidation pathway,and increased expression of CPT1A and ACOX1(P<0.01).Co-IP results showed that the binding between SRC-3 and PPARα was decreased in the SRC-3-IN-1 groups compared with the model group.Conclusion SRC-3-IN-1 ameliorates hepatic lipid metabolism disorders in diabetic mice by activating the PPARα-LXRα-ABCA1 pathway.