ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR

K Schwartz, RM Lawn, DP Wade - Biochemical and biophysical research …, 2000 - Elsevier
K Schwartz, RM Lawn, DP Wade
Biochemical and biophysical research communications, 2000Elsevier
ATP-binding cassette transporter 1 (ABC1) mediates the active efflux of cholesterol from
cells to apolipoproteins. To study the mechanisms of regulation of ABC1 gene expression,
RAW 264.7 macrophages were transiently transfected with ABC1 promoter-luciferase
reporter gene-fusion constructs. Transcription from a 1.64 kb fragment was induced by
cholesterol loading but was not responsive to cAMP. Treatment of the cells with 9-cis retinoic
acid or 20 (S)-hydroxycholesterol, ligands for the nuclear receptors LXR and RXR, resulted …
ATP-binding cassette transporter 1 (ABC1) mediates the active efflux of cholesterol from cells to apolipoproteins. To study the mechanisms of regulation of ABC1 gene expression, RAW 264.7 macrophages were transiently transfected with ABC1 promoter-luciferase reporter gene-fusion constructs. Transcription from a 1.64 kb fragment was induced by cholesterol loading but was not responsive to cAMP. Treatment of the cells with 9-cis retinoic acid or 20(S)-hydroxycholesterol, ligands for the nuclear receptors LXR and RXR, resulted in a marked induction of luciferase expression. The responsible control element was mapped to an imperfect direct repeat of the nuclear receptor half-site TGACCT separated by four bases (DR-4) that binds LXR/RXR heterodimers. Endogenous ABC1 gene expression in RAW cells and apolipoprotein A-I mediated cholesterol efflux were also upregulated by both receptor ligands. These findings raise the possibility that ligands that activate the LXR-RXR heterodimer may be useful for the therapeutic modulation of the ABC1 pathway.
Elsevier