| Although the physiological significance of microsomal fatty acid elongation is well-recognized, the regulation of fatty acid elongase expression remains poorly defined. Of the 6 elongase subtypes expressed in mammals, adult rat liver expresses mRNA encoding 4 elongase subtypes; Elovl-5 > Elovl-1 = Elovl-2 = Elovl-6.;We first examined nutritional and developmental regulation of hepatic fatty acid elongase as well as the role of key transcription factors in the control of hepatic elongase and desaturase expression in rat primary hepatocytes and in liver in vivo. These studies suggested that hepatic elongase expression is controlled by several transcription factors, PPARα, SREBP-1, LXR, ChREBP and MLX. The in vivo studies shows the changes in hepatic lipid composition induced by diabetes or obesity correlated with changes in elongase and desaturase expression.;Even though individual Elovl isoform has different substrate preferences, tissue specific expression, and are regulated differently, the significance of this diversity is unknown. By overexpressing Elovl isoforms in primary hepatocytes, we amplify each elongase function. Overexpression of both Elovl-2 and Elovl-5 enhance 20:5n3 conversion to 22:5n3 or 24:5n3, which leads to reduction of 20:5n3 and thus attenuates 20:5n3 mediated induction on PPARα regulated transcripts. Moreover, overexpression of Elovl-2 can enhance 20:5n3 mediated suppression of SREBP-1c nuclear content but not Elovl-5.;In order to gain a more detailed understanding of the function of these enzymes, the mice overexpressing Elovl-5 by recombinant adenovirus were characterized. Overexpression of Elovl-5 alone has profound effect on hepatic glycogen level as well as blood glucose. The altered gene expression related to glucose metabolism by overexpression of Elovl-5 can partly account for it. In addition, overexpression of Elovl-5 also suppresses the PPARα target genes but no effect on lipogenesis. The changes of fatty acid profile in liver and blood are consistent with Elovl-5 overexpression. Moreover, overexpression of Elovl-5 significantly decreased blood triglyceride during refeeding. This strongly suggests that Elovl-5 play an important role in management of glucose and fatty acid metabolism.;Overall, these studies establish the role for specific transcriptional regulatory networks in the control of hepatic elongase gene expression and hepatic lipid composition. By overexpression of specific fatty acid elongase in vitro and in vivo, our study is the first to show that fatty acid elongases play an important role in glucose metabolism and hepatic function as well as fatty acid metabolism. This finding may contribute to the therapy of metabolic disease, such as diabetes. |
