Cited by 155Liver Disease Diagnosis and TreatmentFatty Acid Research and HealthLiver physiology and pathology

A Maresin 1/Rorα/12-Lipoxygenase Autoregulatory Circuit Prevents Inflammation and Progression of Nonalcoholic Steatohepatitis

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Han, Yong-Hyun, Shin, Kyong-Oh, Kim, Ju-Yeon, Khadka, Daulat B., Kim, Hyeon-Ji, Lee, Yong-Moon, Cho, Won-Jea, Cha, Ji-Young +2 more·2019·Journal of Clinical Investigation

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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  • At least some specialized proresolving mediators including maresins and resolvins are produced by macrophages and signal to macrophages to reduce inflammatory and fibrogenic gene expression.

    “At least some of these lipid metabolites are produced by macrophages (101) and also signal to macrophages to reduce inflammatory and fibrogenic gene expression (102).”

    From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [102]

  • A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of MASH.

    “A maresin 1/ RAR-related orphan receptor alpha (RORα)/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of MASH (102).”

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Research works printed but not linked: 1

  1. Dalli J, et al. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 2013;27(7):2573-2583.

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Authors
Han, Y.-H., Shin, K.-O., Kim, J.-Y., Khadka, D. B., Kim, H.-J., Lee, Y.-M., Cho, W.-J., Cha, J.-Y., Lee, B.-J., & Lee, M.-O.
Affiliations
  • Seoul National University (KR)
  • Chungbuk National University (KR)
  • Chonnam National University (KR)
  • Gachon University (KR)
Corresponding author
Lee, Mi-Ock
Venue
Journal of Clinical Investigation
Published
2019-03-11
Volume
129
Issue
4
Pages
1684-1698
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
OpenAlex
W2921132259
Cited by
154
References
56
Citations by year
2026: 17 · 2025: 16 · 2024: 11 · 2023: 24 · 2022: 37 · 2021: 30 · 2020: 14 · 2019: 5
FWCI
16.37
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • The National Research Foundation of Korea (2017R1A2B3011870, 2018R1A5A2024425)
  • Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073556)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
maresin 1, RORα, 12-lipoxygenase, nonalcoholic steatohepatitis, specialized pro-resolving mediators, docosahexaenoic acid metabolites, M2 macrophages, high-fat diet-induced liver injury, inflammation resolution, therapeutic target
MeSH terms
Animals, Arachidonate 12-Lipoxygenase, Dietary Fats, Docosahexaenoic Acids, Humans, Inflammation, Macrophages, Male, Mice, Knockout, Mice, Nuclear Receptor Subfamily 1, Group F, Member 1, Non-alcoholic Fatty Liver Disease

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