Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha

LXR alpha is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a rol e for this transcription factor in the control of cellular cholesterol effl ux, We demonstrate that retroviral expression of LXR alpha in NIH 3T3 fibro blasts or RAW264.7 macrophages and/or treatment of these cells with oxyster ol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding t he putative cholesterol/phospholipid transporter ATP-binding cassette (ABC) A1, In contrast, induction of ABCA1 mRNA in response to oxysterols is atten uated in cells that constitutively express dominant-negative forms of LXR a lpha or LXR beta that lack the AF2 transcriptional activation domain. We fu rther demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/o r treatment of these cells with oxysterols is sufficient to stimulate chole sterol efflux to extracellular apolipoprotein A1. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibro blasts, which carry a loss of function mutation in the ABCA1 gene. Taken to gether, these results indicate that cellular cholesterol afflux is controll ed, at least in part, at the level of transcription by a nuclear receptor-s ignaling pathway. They suggest a model in which activation of LXRs by oxyst erols in response to cellular sterol loading leads to induction of the ABCA 1 transporter and the stimulation of lipid efflux to extracellular accepter s. These findings have important implications for our understanding of mamm alian cholesterol homeostasis and suggest new opportunities for pharmacolog ical regulation of cellular lipid metabolism.