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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

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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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Figure 7

12-LOX modulates the DHA-mediated improvement of NASH.

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12-LOX modulates the DHA-mediated improvement of NASH.
(A–C) Seven-week-...
(A–C) Seven-week-old WT male C57BL/6 mice were fed with HFD for 12 weeks. After 10 weeks of diet feeding, DHA was i.p. injected daily at dose of 5 mg/kg BW with vehicle or 5 mg/kg BW baicalein for 2 weeks. (A) Representative captured liver tissues and H&E staining of liver sections. Scale bar: 200 μm. (B) Amount of MaR1 in the liver tissues were analyzed. (C) The liver macrophages were isolated from mice and the CD206+/CD80+ ratio of F4/80+ cells was determined by flow cytometry. **P < 0.01; ##P < 0.01 (n = 6–8) for B and C. (D–G) Seven-week-old WT male C57BL/6 mice were fed with HFD for 16 weeks. After 13 weeks of diet feeding, an intravenous injection of either AAV-GFP or AAV–12-LOX at 5 × 109 virus genomes was conducted. DHA was i.p. injected daily at doses 1 mg/kg BW for 3 weeks after virus injection. (D) Representative captured liver tissues and the liver weights at the end of experiments. (E) Sirius red staining of liver sections. Fibrotic area in the liver sections was analyzed by Image J. Scale bar: 50 μm. (F) Levels of α-SMA, TGF-β, and 12-LOX proteins in the liver tissues were analyzed by Western blotting. (G) The amount of MaR1 in liver tissues were measured. *P < 0.05, #P < 0.05, and ##P < 0.01 (n = 5) for D–G. (H) Isolated liver macrophages were treated with 50 μM DHA and then infected by AAV-GFP or AAV–12-LOX. The CD206+/CD80+ ratio of F4/80+ cells was determined. *P < 0.05, #P < 0.05 (n = 3). The data represent mean ± SD. Data were analyzed by Mann–Whitney U test for simple comparisons or Kruskal-Wallis test for multiple groups.

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