Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner
Yulian Chen, Huanguo Jiang, Zhikun Zhan, Jindi Lu, Tanwei Gu, Ping Yu, Weimin Liang, Xi Zhang, Shilong Zhong, Lan Tang
Abstract
Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that oridonin exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between TG and PE by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that oridonin contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα−dependent manner, whose results were shown as TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after oridonin treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of oridonin in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα−ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.