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

Retinoic acid-related orphan receptor alpha (ROR alpha) 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 alpha as a polarity regulator were largely unknown. Here, we identified maresin 1 (MaR1), a docosahexaenoic acid (01-1A) metabolite with a function of specialized proresolving mediator, as an endogenous ligand of ROR alpha. MaR1 enhanced the expression and transcriptional activity of ROR alpha. and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet-induced NASH in a ROR alpha-dependent manner. Surprisingly, ROR alpha 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 alpha/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH.