Abstract
The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) 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−/− mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) 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 DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2−/− mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.
Highlights
The potential role of endogenously synthesized PUFAs is a highly overlooked area
We observed an accumulation of the omega-6 fatty acids 20:4n-6 and 22:4n-6, as well as the omega-3 fatty acids 20:5 (EPA) and 22:5n-3, in both liver and serum of Elovl KO mice compared with wild-type littermates
By generating Elovl2-deficient mice, we have recently shown that the ELOVL2 enzyme is required for the elongation of PUFAs of the omega-6 family in testis into C26 PUFAs, which are essential precursors for further elongation by ELOVL4 into C28–C30 carbon atoms that are indispensable for normal sperm formation and fertility in mice [16]
Summary
The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very longchain fatty acids (ELOVLs) 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؊/؊ mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24carbon precursors for DHA and DPAn-6 formation in vivo. Elovl ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice. Dietary PUFAs, and especially DHA, have been shown to influence hepatic liver metabolism and prevent the development of liver steatosis [1,2,3,4]. The role of endogenously synthesized PUFAs compared with PUFAs taken up from the diet is relatively unknown
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