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Δ-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators
Open accessAbstract
Objective—: Human genetic variants near the FADS (fatty acid desaturase) gene cluster ( FADS1-2 - 3 ) are strongly associated with cardiometabolic traits including dyslipidemia, fatty liver, type 2 diabetes mellitus, and coronary artery disease. However, mechanisms underlying these genetic associations are unclear. Approach and Results—: Here, we specifically investigated the physiological role of the Δ-5 desaturase FADS1 in regulating diet-induced cardiometabolic phenotypes by treating hyperlipidemic LDLR (low-density lipoprotein receptor)-null mice with antisense oligonucleotides targeting the selective knockdown of Fads1 . Fads1 knockdown resulted in striking reorganization of both ω-6 and ω-3 polyunsaturated fatty acid levels and their associated proinflammatory and proresolving lipid mediators in a highly diet-specific manner. Loss of Fads1 activity promoted hepatic inflammation and atherosclerosis, yet was associated with suppression of hepatic lipogenesis. Fads1 knockdown in isolated macrophages promoted classic M1 activation, whereas suppressing alternative M2 activation programs, and also altered systemic and tissue inflammatory responses in vivo. Finally, the ability of Fads1 to reciprocally regulate lipogenesis and inflammation may rely in part on its role as an effector of liver X receptor signaling. Conclusions—: These results position Fads1 as an underappreciated regulator of inflammation initiation and resolution, and suggest that endogenously synthesized arachidonic acid and eicosapentaenoic acid are key determinates of inflammatory disease progression and liver X receptor signaling.
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“hyperlip-idaemic mice with knockdown of the gene encoding fatty acid desaturase 1, an enzyme involved in the biosynthesis of arachidonic acid and EPA, have an increased atherosclerosis burden associated with a pronounced decrease in the SPM:leukotriene ratio128.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [128]
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“in mice fed a diet enriched in omega-3 polyunsaturated fatty acids, endogenous arachidonic acid and EPA production through desaturation of the upstream precursor omega-6 and omega-3 fatty acids, respectively, are needed to favour SPM formation128.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [128]
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Metadata
- Authors
- Gromovsky, A. D., Schugar, R. C., Brown, A. L., Helsley, R. N., Burrows, A. C., Ferguson, D., Zhang, R., Sansbury, B. E., Lee, R. G., Morton, R. E., Allende, D. S., Parks, J. S., Spite, M., & Brown, J. M.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2018-01
- Volume
- 38
- Issue
- 1
- Pages
- 218-231
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC5746431
- OpenAlex
- W2766145247
- Cited by
- 115
- References
- 50
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 10 · 2023: 17 · 2022: 12 · 2021: 19 · 2020: 17 · 2019: 10 · 2018: 8
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (4u01aa021893-05, UL1TR000439)
- National Institute on Alcohol Abuse and Alcoholism (U01-AA021893, P50AA024333)
- National Heart, Lung, and Blood Institute (F32HL136044, R01HL119962, R01HL106173, R01HL122283)
- National Cancer Institute (P30CA043703)
- National Institute of General Medical Sciences (P01GM095467)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103637, U01DK061732)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- FADS1, omega-6 fatty acids, omega-3 polyunsaturated fatty acids, specialized pro-resolving mediators, liver inflammation, atherosclerosis, hepatic lipogenesis, macrophage polarization, arachidonic acid, eicosapentaenoic acid, hyperlipidemia, cardiometabolic disease
- MeSH terms
- Liver X Receptors, Delta-5 Fatty Acid Desaturase, Animals, Aorta, Aortic Diseases, Cells, Cultured, Disease Models, Animal, Inflammation, Liver, Macrophage Activation, Mice, Inbred C57BL, Receptors, LDL, Eicosapentaenoic Acid, Oligonucleotides, Antisense, Arachidonic Acid, Macrophages, Peritoneal, Mice, Knockout, Inflammation Mediators, Fatty Acid Desaturases, Lipogenesis, Dyslipidemias, Atherosclerosis, Plaque, Atherosclerotic
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