Oleanolic Acid Up-Regulated UGT1A1 and Antagonized Inflammation by Affecting the Binding of PXR and PKCα to HSP90α and SRC1.

Our previous studies have demonstrated that oleanolic acid (OA) can induce UGT1A1 expression in HepG2 cells by activating PXR and alleviate inflammatory damage caused by alpha-naphthyl isothiocyanate (ANIT). Activation of PKCα by phorbol-12-myristate-13-acetate (PMA) can significantly down-regulate the expression of UGT1A1 and counteract the inductive effect of OA on UGT1A1. This study aimed to explore the molecular mechanism of OA in up-regulating UGT1A1 and antagonizing inflammation based on the interaction of PXR and PKCα with HSP90α and SRC1. The expressions of PKCα, PXR, and UGT1A1, and the binding of PKCα and PXR to HSP90α and SRC1 were detected in HepG2 cells and in rats. The activation of PKCα induced by PMA or ANIT led to hyperinflammatory response and increased transfer of PKCα to the membrane, accompanied by decreased binding of PKCα to HSP90α and increased binding of PXR to HSP90α in the cytoplasm, which decreased the nuclear translocation of PXR and its binding to SRC1, and finally down-regulated the expression of UGT1A1. OA significantly inhibited the transfer of PKCα to cell membrane induced by PMA or ANIT, resulting in increased binding of PKCα to HSP90α and decreased binding of HSP90α to PXR in the cytoplasm. This facilitates PXR to enter the nucleus and increases its binding with SRC1, up-regulates UGT1A1 expression and inhibits inflammatory response. OA can affect the binding of PXR and PKCα with HSP90α and SRC1 to up-regulate the expression of UGT1A1 and finally antagonize inflammatory injury.