Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice

The potential role of endogenously synthesized polyunsaturated fatty acids (PUFAs) is a highly overlooked area. Elongation of very long chain (ELOVL) fatty acids in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2 ablated mice displayed substantial decreased levels of 22:6(n3), docosahexaenoic acid (DHA), and 22:5(n6), docosapentaenoic acid (DPAn6), followed by an accumulation of 22:5(n3) and 22:4(n6) in both liver and serum showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24 carbon precursors for DHA and DPA(n6) formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol regulatory element binding protein 1c (SREBP1c) as well as its downstream target genes. Surprisingly, the Elovl2 ablated mice were resistant against hepatic steatosis and diet induced weight gain implying that hepatic DHA synthesis via ELOVL2, except controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP1c independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.