Δ-5 Fatty Acid Desaturase Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators.

OBJECTIVE

Human genetic variants near the FADS (fatty acid desaturase) gene cluster (-) 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 . 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 activity promoted hepatic inflammation and atherosclerosis, yet was associated with suppression of hepatic lipogenesis. 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 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 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.