Metabolic Significance of Fatty Acid Elongation

University dissertation from Stockholm : Department of Physiology, Stockholm University

Abstract: Very long-chain fatty acids (VLCFAs), including polyunsaturated fatty acids (PUFAs), are essential lipids whose functional diversity is made possible by variation in their chain length and degree of unsaturation. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis, up to 16 carbons in length by fatty acid synthase. Further elongation into VLCFAs is catalysed by the enzymes referred to as elongation of very long-chain fatty acids (ELOVLs). Seven ELOVL proteins have been identified, all of which display distinct fatty acid substrate specificity. The enclosed papers discuss issues regarding the regulation, function and contribution to lipid composition of the Elovl genes with special emphasis on Elovl2 and Elovl3.In primary brown adipocytes the Elovl3 gene was shown to be regulated by all three PPAR isoforms, involving both transcriptional activation and mRNA stability. In an attempt to clarify the role of ELOVL3 in whole-body lipid homeostasis, the metabolic effects associated with Elovl3 ablation in mice were investigated. Elovl3-ablated mice were lean and showed markedly reduced triglyceride and leptin levels in serum. In addition, the mice were completely resistant to diet-induced obesity, associated with a reduced hepatic lipogenic gene expression and triglyceride content.Over-expression of Elovl2 in cells promoted accumulation of lipid droplets, associated with enhanced fatty acid uptake and induction of PPAR? target genes. To further assess the in vivo function of ELOVL2, the Elovl2 gene was disrupted in mice by homologous recombination. Elovl2-ablated mice exhibited a severe reduction of the elongation products of C24:5n-6 in the testis, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs ?C26. In addition, Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify an indispensable function of ELOVL2-derived fatty acids, which can give new insights into nutritional intervention as an aid in assisting male fertility problems.