Elovl3 and very long chain fatty acids; role in metabolism

Sammanfattning: Fatty acids (FA) are important in several aspects of cellular function, for example as structural molecules and metabolic substrates. The bulk of FA up to 16 carbons (palmitic acid) in length are synthesised by a cytosolic enzyme complex called fatty acid synthase (FAS), while FA can be further elongated into very long-chain fatty acids (VLCFA) by membrane-bound enzymes in the endoplasmatic reticulum (ER). Individual enzymes perform the four different steps of the elongation cycle to extend VLCFA, where condensation enzymes (first step) are suggested to be rate-limiting as well as in control of substrate specificity. Six mammalian condensation enzymes, encoded by Elovl (Elogation of very long chain fatty acids) genes in mouse, have presently been identified which suggests multiple elongation pathways.In this report, I present data from studies performed mainly in brown adipose tissue and skin on the role of ELOVL3 in metabolic and structure-related processes. This enzyme is suggested to be involved in the synthesis of saturated and monounsaturated VLCFA, which are incorporated into different classes of lipids. Acyl-specific structural functions of sphingolipids, essential for proper membrane integrity, constitute a requirement for endogenous synthesis of VLCFA. We have demonstrated complementary functions between yeast and murine elongation enzymes in the synthesis of sphingolipids with corresponding alterations in cell viability. This indicates a conserved function for elongation enzymes in eukaryotic cells, which implicates cellular growth and maintenance of membrane structures.Investigations of the lipid composition in Elovl3-ablated mice, generated by homologous recombination, support a role for ELOVL3 in the synthesis of neutral lipids, such as triglycerides and sterol-esters. The phenotype of these mice includes impaired skin barrier function and altered VLCFA elongation activity in liver and brown adipose tissue, which is consistent with the tissue-specific expression pattern of this gene.Regulation of Elovl3 mRNA expression in brown adipocytes was found to differ from what was seen for other Elovl gene family members, which suggests divergent functional roles within the family of elongases. Elovl3 expression correlated with a high oxidative state, therefore, the function of this enzyme may be to replenish specific lipids under conditions of intense FA turnover. In addition, channeling of metabolic substrates is altered in brown adipocytes lacking ELOVL3, indicating important functions of specific VLCFA in nutritional homeostasis and substrate utilization.