한빛사 논문
Yong-Hyun Han,1 Kyong-Oh Shin,4 Ju-Yeon Kim,1 Daulat B. Khadka,5 Hyeon-Ji Kim,1 Yong-Moon Lee,4 Won-Jea Cho,5 Ji-Young Cha,6 Bong-Jin Lee,1 and Mi-Ock Lee1,2,3,*
1 College of Pharmacy and 2 Bio-MAX Institute, 3 Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea. 4 College of Pharmacy, Chungbuk National University, Cheongju, South Korea. 5 College of Pharmacy, Chonnam National University, Gwangju, South Korea. 6 Laboratory of Cell Metabolism and Gene Regulation, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
*Address correspondence to: Mi-Ock Lee, College of Pharmacy, Seoul National University, San 56-1 Sillim-dong, Kwanak-gu, Seoul 08826, South Korea.
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.
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