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A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis
Open accessAbstract
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 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]
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“A maresin 1/ RAR-related orphan receptor alpha (RORα)/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of MASH (102).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [102]
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Metadata
- 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
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2019-03-11
- Volume
- 129
- Issue
- 4
- Pages
- 1684-1698
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6436872
- 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
- bronze
- doi.org
- 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 › Hepatology › 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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