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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 Article has an altmetric score of 8

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 8

Expression of 12-LOX in liver macrophages is significantly low in the human patients with NASH.

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Expression of 12-LOX in liver macrophages is significantly low in the hu...
(A) Gene expression analysis was conducted using public data sets obtained from GEO site at the NCBI (http://www.ncbi.nlm.nih.gov/geo/). The data processed as quantile normalized intensity value. Significances were analyzed by Mann-Whitney U test, and the positive correlation coefficient (r) was calculated by Pearson correlation test for healthy controls (n = 24) and NASH patients (n = 19); *P < 0.05. (B) Immunohistochemistry staining of 12-LOX in the liver specimens of the Biomax human tissue array is shown. The 12-LOX positive area was analyzed by Image J. *P < 0.05 (n = 10 for healthy controls; n = 7 for chronic hepatitis without B virus). Scale bar: 15 μm. For quantification, 8 fields of each specimen were analyzed. (C) Expression of 12-LOX and CD68 was visualized by red and green immunofluorescence in the liver specimens of the Biomax human tissue array. The nuclei were stained by DAPI that indicate nuclei of all the parenchymal and nonparenchymal liver cells. Colocalization of 12-LOX and CD68 were assessed by yellow colored dots that counted from at least 5 images per tissue using Image J software (n = 17 for healthy controls; n = 15 for chronic hepatitis without B virus). **P < 0.01. Scale bar: 40 μm. (D) THP-1 cells were treated with 200 nM MaR1 or 5 μM SR1078 for 24 hours. The mRNA levels of RORA, ALOX12, and ALOX15 were analyzed by qRT-PCR. *P < 0.05 (n = 3). The data represent mean ± SD. Data were analyzed by Mann–Whitney U test for simple comparisons. (E) Schematic model for the mechanism of MaR1/RORα/12-LOX autoregulatory circuit for M2 polarity switch in the liver macrophages.

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