The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.
UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis
Open accessAbstract
Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1-dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1β and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro-IL-1β gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.
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“the uncoupling protein 2, a driver for fatty acid synthesis, activates NLRP3 inflammasome [70].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [70]
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- Zhang, 2008, Curr Protoc Immunol., Chapter 14, Unit 14.1
- 10.1371/journal.pmed.1001577 · DOI · Paper page
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Metadata
- Authors
- Moon, J.-S., Lee, S., Park, M.-A., Siempos, I. I., Haslip, M., Lee, P. J., Yun, M., Kim, C. K., Howrylak, J., Ryter, S. W., Nakahira, K., & Choi, A. M. K.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- Brigham and Women's Hospital (US)
- Yale University (US)
- Pennsylvania State University (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-01-09
- Volume
- 125
- Issue
- 2
- Pages
- 665-680
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4319445
- OpenAlex
- W2064173000
- Cited by
- 238
- References
- 70
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 16 · 2023: 23 · 2022: 26 · 2021: 33 · 2020: 32 · 2019: 24 · 2018: 24 · 2017: 28 · 2016: 15 · 2015: 9
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-03-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Strong
- European Society of Intensive Care Medicine
- National Institutes of Health
- College of Veterinary Medicine, Cornell University
- Weill Cornell Medical College
- National Heart, Lung, and Blood Institute (R01HL055330, R01HL079904, P01HL108801, R01HL060234, R01HL112747, P01HL114501)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- UCP2, fatty acid synthase, NLRP3 inflammasome, sepsis, macrophages, lipid metabolism, caspase-1 activation, IL-1β, IL-18, lipopolysaccharide, mitochondrial uncoupling, cerulenin, C75, therapeutic target
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Uncoupling Protein 2, Animals, Carrier Proteins, Enzyme Induction, Humans, Ion Channels, Lipids, Macrophages, Down-Regulation, Mice, Knockout, Sepsis, Caspase 1, Interleukin-18, Mitochondrial Proteins, Mice, Interleukin-1beta, Fatty Acid Synthase, Type I, Inflammasomes
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