Anthony D Gromovsky1, Rebecca C Schugar1, Amanda L Brown1, Robert N Helsley1, Amy C Burrows1, Daniel Ferguson1, Renliang Zhang1, Brian E Sansbury1, Richard G Lee1, Richard E Morton1, Daniela S Allende1, John S Parks1, Matthew Spite1, J Mark Brown2. 1. From the Department of Cellular and Molecular Medicine, Lerner Research Institute (A.D.G., R.C.S., A.L.B., R.N.H., A.C.B., D.F., R.Z., R.E.M., J.M.B.) and Department of Anatomical Pathology (D.S.A.), Cleveland Clinic, OH; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (B.E.S., M.S.); Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA (R.G.L.); and Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.). 2. From the Department of Cellular and Molecular Medicine, Lerner Research Institute (A.D.G., R.C.S., A.L.B., R.N.H., A.C.B., D.F., R.Z., R.E.M., J.M.B.) and Department of Anatomical Pathology (D.S.A.), Cleveland Clinic, OH; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (B.E.S., M.S.); Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA (R.G.L.); and Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.). brownm5@ccf.org.
Abstract
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.
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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