Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice.
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.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden; and.
Anna M
AM
Pauter
Petter
P
Olsson
Abolfazl
A
Asadi
Bengt
B
Herslöf
Robert I
RI
Csikasz
Damir
D
Zadravec
Anders
A
Jacobsson
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000097:blood*; D000081031:Fatty Acid Elongases; D005234:Fatty Liver / Q000201:enzymology; D006706:Homeostasis; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism
C000630951:ELOVL2 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D004281:Docosahexaenoic Acids; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
docosahexaenoic acid; elongase of very long-chain fatty acid 2; fatty acid elongase; liver steatosis; weight gain