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

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 unk...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of clinical investigation Vol. 130; no. 4; pp. 1684 - 1698
Main Authors Han, Yong-Hyun, Shin, Kyong-Oh, Kim, Ju-Yeon, Khadka, Daulat B, Kim, Hyeon-Ji, Lee, Yong-Moon, Cho, Won-Jea, Cha, Ji-Young, Lee, Bong-Jin, Lee, Mi-Ock
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 01.04.2019
Subjects
Arachidonate 12-lipoxygenase
Biomedical research
Biosynthesis
Cytokines
Docosahexaenoic acid
Fatty acids
Genotype & phenotype
High fat diet
Inflammation
Ligands
Lipids
Lipoxygenase
Liver
Liver diseases
Macrophages
Metabolic disorders
Metabolites
Microenvironments
Obesity
Pathogenesis
Polarity
Retinoic acid
Transcription
Tumor necrosis factor-TNF
Hepatitis
Molecular pathology
Inflammation
Macrophages
Hepatology
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI124219