A maresin 1/ROR?/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis.

ABSTRACT: Retinoic acid-related orphan receptor ? (ROR?) is considered a key regulator of polarization in liver macrophages that is closely related to nonalcoholic steatohepatitis (NASH) pathogenesis. However, hepatic microenvironments that support the function of ROR? as a polarity regulator were largely unknown. Here, we identified maresin 1 (MaR1), a docosahexaenoic acid (DHA) metabolite with a function of specialized proresolving mediator, as an endogenous ligand of ROR?. MaR1 enhanced the expression and transcriptional activity of ROR? and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet-induced NASH in a ROR?-dependent manner. Surprisingly, ROR? increased the level of MaR1 through transcriptional induction of 12-lipoxygenase (12-LOX), a key enzyme in MaR1 biosynthesis. Furthermore, we demonstrated that modulation of 12-LOX activity enhanced the protective function of DHA against NASH. Together, these results suggest that the MaR1/ROR?/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH.

SUBMITTER: Han YH 

PROVIDER: S-EPMC6436872 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature