Metabolic Significance of Systemic DHA Deficiency

Sammanfattning: Fatty acid composition in the body displays a high level of heterogeneity and can rapidly respond to changes in diet regime or to starvation. Homeostasis of the level of certain fatty acids is an important factor for maintenance of structural integrity as well as for proper signaling within the organism. Hence, changes in fatty acid composition have been proposed as an important factor during the pathogenesis of many diseases.Concentration of polyunsaturated fatty acid (PUFA) within the body is modulated by the interplay between dietary intake, endogenous de novo synthesis or mobilization of fatty acids from tissue reservoirs. Endogenous synthesis of PUFA is regulated on different genetic levels as well as the level of substrate availability. Studies have reported a variation in PUFA biosynthesis between different developmental stages, age, gender, during pregnancy, lactation and under conditions of certain disorders. A member of the enzymatic machinery involved in PUFA synthesis is the elongase Elongation of very long-chain fatty acids 2 (ELOVL2) that controls the elongation of PUFA with 22 carbons to produce 24 carbons precursors for the production of the omega-3 PUFA, docosahexaenoic acid (DHA, 22:6n3) and the omega-6 PUFA, docosapentaenoic (DPAn6, 22:5n6). Deletion of Elovl2 in a mouse model (Elovl2KO) leads to systemic DHA deficiency at different physiological and early lifestages, and is related to certain metabolic dysfunctions. Mitochondria of Elovl2KO mice display structural and functional impairment. Compared to wild type littermates, Elovl2KO mice do not gain as much weight after high-fat diet treatment and do not develop hepatic steatosis, despite having a higher level of the positive regulator of denovo lipogenesis, nuclear transcription factor SREBP1c. Resistance to high fat diet induced-obesity in Elovl2KO mice is abolished by DHA supplementation together with high sucrose content in the background diet. In conclusion, deletion of Elovl2 in mice leads to systemic DHA deficiency that has pleiotropic effect on mouse energy metabolism.