Regulation of Elovl and fatty acid metabolism

Fatty acids are important regulators in the control of mammalian energy homeostasis. They are ingested in the diet but a significant amount are also endogenously produced by de novo lipogenesis. Fatty acid elongation beyond 16 carbons (palmitic acid) can occur to generate very long chain fatty acids (VLCFA), a process that is initiated by the rate-limiting condensation reaction. To date, six mammalian enzymes responsible for this reaction, ELOVL1-6 (Elongation of very long chain fatty acid), have been characterized. All of them exert substrate specificity and tissue-specific gene expression. In this thesis, factors that regulate fatty acid metabolism and, in particular, fatty acid synthesis and elongation will be presented. The enclosed papers discuss issues as to how Elovl3 is regulated in liver and in different adipose depots and what effects ablation of this enzyme causes to lipid homeostasis. In contrast to the expression of several other lipogenic genes, Elovl3 gene expression was not affected by fasting or refeeding. Instead, the gene expression was influenced by steroid hormones such as glucocorticoids and sex hormones. Also, hepatic Elovl3 gene expression followed a circadian rhythm, present exclusively in sexually mature male mice. Interestingly, despite reduced levels of leptin, Elovl3-ablated mice were shown to be resistant to diet induced weight gain, which seemed to be due to a decreased ratio between energy intake and energy expenditure. This phenotype was more pronounced in female mice. This thesis is based on the following papers, which are referred to in the text by their respective Roman numerals I-IV. I. Brolinson, A., Fourcade, S., Jakobsson, A., Pujol, A. and Jacobsson, A. (2008) Steroid hormones control circadian Elovl3 expression in mouse liver. Endocrinology 149(6):3158-3166. II. Brolinson, A., Zadravec, D., Fisher, R.M., Carneheim, C., Csikasz, R., Borén, J., Rudling, M. and Jacobsson, A. (2009) Ablation of the very long chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity.