Oltipraz inhibits liver X receptor‐alpha‐dependent lipogenic gene induction and hepatic steatosis via AMPK‐S6K1 pathway

Abstract

Nonalcoholic fatty liver disease is closely associated with metabolic syndrome and insulin resistance. This study investigated the role of S6K1 in LXRalpha activation and the effects of oltipraz on LXRalpha‐dependent lipogenesis in hepatocytes and high‐fat diet animal model. Oltipraz prevented the ability of T0901317 to activate SREBP‐1c, inhibiting its own mRNA and protein induction. The inhibition of S6K1 by oltipraz contributes to the repression of SREBP‐1c induction, whereas S6K1 activation antagonized this inhibitory effect. AMPK, whose activation leads to S6K1 inhibition, contributes to inhibit the induction of SREBP‐1c by T0901317. Oltipraz impaired T0901317‐induced CYP7A1 transactivation. Moreover, S6K1 and AMPK oppositely regulate LXRalpha activity through their phosphorylations at different residues. S6K1 inhibition antagonized CYP7A1 induction promoted by AMPK inhibition, whereas AMPK activation abrogated S6K1‐dependent CYP7A1 induction, supporting the opposing role of S6K1 and AMPK in LXR activity. Consistently, oltipraz inhibited hepatic triglyceride accumulation and lipogenic gene induction in mice. Our findings showing the role of AMPK‐S6K1 pathway in LXRalpha activity and S6K1‐dependent inhibition of LXRalpha‐induced lipogenic gene transactivation by oltipraz led to the identification of S6K1 as an attractive target for intervention in hepatic steatosis.