Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR alpha and LXR beta

The liver X receptors (LXRs) are members of the nuclear hormone receptor su perfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that cont rol intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory elem ent-binding protein-lc gene (SREBP-1c), which encodes a membrane-bound tran scription factor of the basic helix-loop-helix-leucine zipper family. SREBP -1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its h eterodimer partner, the retinoid X receptor (RXR). Expression of the relate d gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is e ssential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nucle ar, active form of the SREBP-1c protein and an increase in fatty acid synth esis. Because this active form of SREBP-1c controls the transcription of ge nes involved in fatty acid biosynthesis, our results reveal a unique regula tory interplay between cholesterol and fatty acid metabolism.