Oxymatrine relieves non-alcoholic fatty liver disease by promoting the sirtuin 1/adenosine 5‘-monophosphate-activated protein kinase pathway and peroxisome proliferator activated receptor alpha-mediated hepatic fatty acid oxidation

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a liver disease without approved treatment. Oxymatrine (OMT) has protective effects in various liver diseases. We aimed to investigate the roles and mechanisms of OMT in NAFLD. NAFLD models were established using high-fat and high-sucrose diet-fed rats and oleic acid (OA)-stimulated hepatocytes, respectively. Then, OMT was used to treat the NAFLD models, with metformin as a positive control. Liver damage, lipid accumulation and hepatic lipid profile of NAFLD rats were assessed. Peroxisome proliferator activated receptor alpha (PPARα), sirtuin 1 (Sirt1)/adenosine 5‘-monophosphate-activated protein kinase (AMPK) pathway- and fatty acid oxidation (acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A)-associated proteins were measured both in vivo and in vitro. Furthermore, hepatocytes were transfected with si-Sirt1 and oe-PPARα to verify the mechanisms of OMT in NAFLD. NAFLD rats supplemented with OMT displayed reduced liver damage and lipid accumulation. After OMT intervention, the liver lipid profile of NAFLD rats was changed greatly, most of the top differentially expressed lipid metabolites were triglyceride, moreover, diacylglycerol content was decreased in NAFLD rats. OMT activated the Sirt1/AMPK pathway and PPARα, and upregulated acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A expressions in NAFLD models. In vitro, OMT enhanced viability, and improved lipid accumulation in OA-stimulated hepatocytes. However, the protective functions of OMT in OA-exposed hepatocytes were offset by Sirt1 knockdown, while PPARα overexpression further counteracted the effects of Sirt1 knockdown. OMT could relieve NAFLD by promoting Sirt1/AMPK pathway- and PPARα-mediated hepatic fatty acid oxidation, indicating that OMT is a potential approach for NAFLD treatment.