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

YH Han, KO Shin, JY Kim, DB Khadka… - The Journal of …, 2019 - Am Soc Clin Investig
YH Han, KO Shin, JY Kim, DB Khadka, HJ Kim, YM Lee, WJ Cho, JY Cha, BJ Lee, MO Lee
The Journal of clinical investigation, 2019Am Soc Clin Investig
Retinoic acid–related orphan receptor α (RORα) 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
RORα 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 RORα. MaR1 enhanced the expression and …
Retinoic acid–related orphan receptor α (RORα) 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 RORα 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 RORα. MaR1 enhanced the expression and transcriptional activity of RORα and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet–induced NASH in a RORα-dependent manner. Surprisingly, RORα 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/RORα/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH.
The Journal of Clinical Investigation