Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2‐related factor 2 (Nrf2). OA derivatives, such as CDDO‐Im and CDDO‐Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G‐protein‐coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long‐term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA‐type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO‐Im and CDDO‐Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.