Hypericin attenuates nonalcoholic fatty liver disease and abnormal lipid metabolism via the PKA-mediated AMPK signaling pathway in vitro and in vivo

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and constitutes a major risk factor for progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). The occurrence of NAFLD is closely associated with abnormal lipid metabolism and implies a high risk of type 2 diabetes and cardiovascular disease. Therefore, specific and effective drugs for the prevention and treatment of NAFLD are necessary. Hypericin (HP) is one of the main active ingredients of Hypericum perforatum L., and we previously revealed its protective role in islet beta-cells and its effects against type 2 diabetes. In this study, we aimed to explore the preventive and therapeutic effects of HP against NAFLD and the underlying mechanisms in vitro and in vivo. Here, we demonstrated that HP improved cell viability by reducing apoptosis and attenuated lipid accumulation in hepatocytes both in vitro and in vivovia attenuating oxidative stress, inhibiting lipogenesis and enhancing lipid oxidization. Thus, HP exhibited significant preventive and therapeutic effects against HFHS-induced NAFLD and dyslipidemia in mice. Furthermore, we demonstrated that HP directly bound to PKAC alpha and activated PKA/AMPK signaling to elicit its effects against NAFLD, suggesting that PKAC alpha is one of the drug targets of HP. In addition, the enhancing effect of HP on lipolysis in adipocytes through the activation of PKAC alpha was also elucidated. Together, the conclusions indicated that HP, of which one of the targets is PKAC alpha, has the potential to be used as a preventive or therapeutic drug against NAFLD or abnormal lipid metabolism in the future.