A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis
Yong-Hyun Han, … , Bong-Jin Lee, Mi-Ock Lee
Yong-Hyun Han, … , Bong-Jin Lee, Mi-Ock Lee
Published March 11, 2019
Citation Information: J Clin Invest. 2019;129(4):1684-1698. https://doi.org/10.1172/JCI124219.
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Research Article Hepatology Inflammation

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

Abstract

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.

Authors

Yong-Hyun Han, Kyong-Oh Shin, Ju-Yeon Kim, Daulat B. Khadka, Hyeon-Ji Kim, Yong-Moon Lee, Won-Jea Cho, Ji-Young Cha, Bong-Jin Lee, Mi-Ock Lee

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