A Novel Orally Available Delta-5 Desaturase Inhibitor Prevents Atherosclerotic Lesions Accompanied by Changes in Fatty Acid Composition and Eicosanoid Production in ApoE Knockout Mice

Abstract

Delta-5 desaturase (D5D), encoded by fatty acid desaturase 1 (Fads1), is the rate-limiting enzyme for the conversion from dihomo-g-linolenic acid (DGLA) to arachidonic acid (AA) in the v-6 polyunsaturated fatty acid pathway. Several AA-derived eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes) and DGLA-derived eicosanoids are reported to promote and/or prevent atherosclerosis progression through, at least in part, its proinflammatory or anti-inflammatory effects. To elucidate the effects of D5D inhibition by a D5D inhibitor on atherosclerosis, we generated a potent, orally available and selective D5D inhibitor, 2-(2,2,3,3,3-Pentafluoropropoxy)-3-[4-(2,2,2-trifluoroethoxy) phenyl]-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione, compound-326, and examined its effects on Western-diet fed ApoE knockout (KO) mice. Oral administration of compound-326 (3-10 mg/kg per day for 15 weeks) significantly inhibited the progression of atherosclerotic lesions in the aorta without affecting plasma total cholesterol and triglyceride levels. Compound-326 significantly decreased AA levels, while it increased DGLA levels in the liver and the blood accompanied by decreases in AA-derived eicosanoid production and increases in DGLA-derived eicosanoid production from the blood cells. We conclude that compound-326 prevents the progression of atherosclerosis in Western-diet fed ApoE KO mice by modulating a profile of eicosanoid production, suggesting that D5D inhibitors can be a novel remedy for preventing atherosclerosis and subsequent cardiovascular events. SIGNIFICANCE STATEMENT This study shows a D5D-specific and orally available potent inhibitor provided the first evidence to support the concept that D5D inhibitors will be a novel remedy for preventing the progression of atherosclerosis.

Fatty acids and aortic valve stenosis

“…AA lipids are abundant in stenotic aortic valves [45]. Inhibiting the D5D in mice fed a western diet promotes amelioration of the atherosclerosis burden [59] which support the hypothesis that D5D-generated AA is indeed important for lipid-driven inflammation. Moreover, phospholipase A2 (PLA2) is responsible for making AA available for downstream metabolism.…”

Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

“…Also we have demonstrated that CSCs have a high dependence on FADS1 and FADS2 function to proliferate and maintain self-renewal. There are multiple commercial or published FADS1/2 or PUFA inhibitors including: CP 24,879 [ 53 , 54 ]; 8,11-Eicosadiynoic Acid [ 55 ]; and compound-326 [ 56 , 57 ]. Our work suggests that targeting PUFA synthesis in GBM with these or other improved FADS inhibitors may have therapeutic benefit in GBM.…”