Glucocorticoid response and promoter occupancy of the mouse LXRalpha gene

The liver X receptors alpha and beta (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily of proteins which are highly expressed in metabolically active tissues. They regulate gene expression of critical genes involved in cholesterol catabolism and transport, lipid and triglyceride biosynthesis, and carbohydrate metabolism in response to distinct oxysterol intermediates in the cholesterol metabolic pathway. Several LXR target genes have been identified, but there is limited information on how expression of the LXRs themselves is controlled. In this study we have characterized the upstream flanking region of the mouse LXRalpha gene. Transient transfections show that the LXRalpha promoter is able to drive transcription of a luciferase reporter gene, however, the transcriptional potential of the promoter in the cell lines used was low. The -2143 to -1513 region of the promoter mediates repression of reporter gene activity in all cells analyzed and multiple DNA-protein interactions were detected in this region by DNase I footprinting. The Zta, Ets, and Hes1 transcription factors were all shown to mediate alterations in reporter gene activity driven by LXRalpha promoter deletion constructs. These factors have been linked to cell cycle and differentiation processes suggesting that expression of LXRalpha might be under control of signalling mechanisms regulating cell proliferation. Several putative binding sites of the glucocorticoid receptor (GR) were identified in the LXRalpha promoter and transient cotransfections of the GR and LXRalpha promoter deletion constructs induced reporter gene activity. Addition of dexamethasone, a GR agonist, abolished this effect suggesting cross talk between GR and LXR signalling.