Rhein alleviates hepatic steatosis in NAFLD mice by activating the AMPK/ACC/SREBP1 pathway to enhance lipid metabolism

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common metabolic liver disorder characterized by excessive lipid accumulation. The 5’-adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC)/sterol regulatory element-binding protein 1 (SREBP1) pathway plays a pivotal role in regulating lipid metabolism. Rhein, a natural compound, has demonstrated hepatoprotective potential; however, its mechanism of action in NAFLD remains unclear. This study aimed to investigate whether rhein ameliorates NAFLD through modulation of the AMPK/ACC/SREBP1 pathway. Methods A murine NAFLD model was established using a high-fat diet (HFD). Mice were treated with varying doses of rhein, and their body weight, liver, kidney, and retroperitoneal fat weights were recorded. Liver pathology was assessed by histological examination and Oil Red O staining. Serum lipid profiles, liver function biomarkers, and inflammatory cytokine levels were measured. Western blotting was employed to analyze the expression and phosphorylation of AMPK pathway-related proteins (AMPK, ACC, and SREBP1). To validate the involvement of this pathway, AMPK-IN-3 was intraperitoneally administered in combination with high-dose rhein to a subset of HFD-fed mice. Results Rhein treatment significantly reduced body weight gain, organ weights, hepatic lipid accumulation, serum cholesterol and triglyceride levels, and the expression of inflammatory cytokines in NAFLD mice. It also improved liver function markers, enhanced AMPK phosphorylation, promoted ACC phosphorylation, and inhibited SREBP1 expression. Notably, co-treatment with AMPK-IN-3 attenuated these beneficial effects, confirming the mechanistic involvement of the AMPK/ACC/SREBP1 pathway. Conclusion Rhein confers protective effects against HFD-induced NAFLD by activating the AMPK/ACC/SREBP1 signaling pathway, thereby enhancing hepatic lipid metabolism, reducing steatosis, and alleviating liver injury and inflammation. These findings suggest that rhein may serve as a promising therapeutic candidate for NAFLD.