Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter

In an attempt to identify transcription factors which activate sterol-regul atory element-binding protein Ic (SREBP-1c) transcription, we screened an e xpression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXR alpha) and LX R beta as strong activators of the mouse SREBP-1c promoter. In the transfec tion studies, expression of either LXR alpha or -beta activated the SREBP-1 c promoter-luciferase gene in a dose-dependent manner. Deletion and mutatio n studies, as well as gel mobility shift assays, located an LXR response el ement complex consisting of two new LXR-binding motifs which showed high si milarity to an LXR response element recently found in the ABC1 gene promote r, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydr oxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic aci d also synergistically activated the SREBP-1c promoter. In HepG2 cells, SRE BP-1c mRNA and precursor protein levels were induced by treatment with 22(R )-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LX R-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c , resulting in activation of the gene for fatty acid synthase, one of its d ownstream genes, as measured by the luciferase assay. These data demonstrat e that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid a nd cholesterol metabolism.