Ursolic Acid Suppresses Fatty Liver-Associated Hepatocellular Carcinoma by Regulating Lipid Metabolism

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and one of the risk factors for hepatocellular carcinoma (HCC). NAFLD-HCC is a metabolic liver injury for which there is a lack of effective treatment. The present study demonstrates the protective effects of Ursolic acid (UA) ameliorating NAFLD-HCC and elucidates the underlying mechanisms. A C57BL/6 male mouse model was fed a high-fat diet (HFD) and injected with diethylnitrosamine (DEN) for 8 months. Ursolic acid (UA) was administered to HFD+DEN mice in order to elucidate the direct involvement of UA in the pathogenesis of NAFLD-HCC. Liver tissue metabolomics was performed by UPLC/Q-TOF-MS. Results revealed that in the HFD+DEN-induced NAFLD-HCC mice model, UA slowed the progressive development of steatosis, steatohepatitis, fibrosis and eventually HCC in mice. UA ameliorates lipid accumulation and liver dysfunction in mice. In addition, UA treatment effectively ameliorated the disturbances in endogenous metabolism induced by HFD+DEN, particularly in glycerophospholipid metabolism. Close relationships were discovered between the lipid metabolism indexes and the differential metabolites, particularly LPA (0:0/16:0), PE (20:0/20:4(5Z,8Z,11Z,14Z)), PC (15:0/20:2(11Z,14Z)), LysoPC (16:1(9Z)). Moreover, UA modified the expression of proteins and mRNA related to lipid metabolism, which could be attributed to fatty acid synthesis (FAS) pathway activation and fatty acid oxidation (FAO) pathway inhibition. This is the first time it has been shown that UA suppresses NAFLD-HCC development by moderating lipid metabolism. The study presents a novel mechanistic explanation for the amelioration of NAFLD-HCC by UA, thereby offering new insights into the prevention and treatment of this condition.