Protein kinase C α modulates liver X receptor α transactivation

Liver X receptor alpha (LXR alpha), an oxysterol-activated nuclear hormone receptor, regulates the expression of genes involved in lipid and cholesterol homeostasis and inflammation. We show here that transactivation by LXR alpha in monkey kidney COS-1 (Cos-1) cells is decreased by activation of the protein kinase C (PKC) signaling pathway. In transient co-transfection assays, phorbol myristate acetate (PMA) suppressed LXR-dependent transactivation of LXR-responsive reporter genes or the natural promoter of the human ATP-binding cassette (ABC), ABCA I gene. The decrease in LXR, transactivation after PMA treatment was also observed in human embryonic kidney (HEK) 293 and human hepatocellular carcinoma (HepG2) cells. Moreover, endogenous LXR target genes, ABCA I and sterol response element-binding protein-1c, were also decreased by PMA treatment in HEK293 cells as assessed by real-time PCR. The PMA-mediated decrease of LXP, activity was blocked by the PKC inhibitor bisindolylmaleimide and mimicked by constitutively active PKC alpha. Nuclear extracts treated with PMA show no decrease in LXR alpha. DNA binding as assessed by mobility shift and chromatin immunoprecipitation assays. Additionally, in vitro kinase assays demonstrate that PKC alpha can phosphorylate LXR alpha. Our findings reveal a mode of regulation of LXR alpha that may be relevant to disease conditions where aberrant PKC signaling is observed, such as diabetes.