Regulation of hepatic fatty acid elongase 5 by LXRα–SREBP-1c

Abstract

Dietary essential fatty acids linoleic acid and α-linolenic acid are converted to arachidonic-, eicosapentaenoic-, and docosahexaenoic acid under tight regulation by nutritional status and hormones. Hepatic fatty acid elongase 5 (Elovl5) elongates C18-20 polyunsaturated fatty acids (PUFAs) and is important for biosynthesis of C20–22 PUFAs. We demonstrate that Liver X Receptor α (LXRα) and sterol regulatory binding protein-1c (SREBP-1c) regulate hepatic Elovl5 expression. LXRα and LXRβ play different roles in maintenance of basal expression of Elovl5. LXRα is necessary for basal as well as LXR agonist induced Elovl5 transcription. Promoter studies revealed that the mouse Elovl5 gene is a direct SREBP-1c target. The up-regulation of Elovl5 expression by LXR agonist is likely secondary to the induction of SREBP-1c. PUFAs repress expression of SREBP-1c and Elovl5, but when combined with LXR ligand stimulation, which increases SREBP-1c mRNA and nuclear SREBP-1c, Elovl5 mRNA levels are restored to normal. Our studies suggest that an LXRα–SREBP-1c pathway plays a regulatory role in hepatic biosynthesis of PUFAs through transcriptional activation of Elovl5 as well as other desaturases. The stimulatory role of LXRα–SREBP-1c in the production of PUFAs enables the possibility for a feedback regulation of hepatic lipogenesis through PUFA mediated repression of SREBP-1c expression.