Liver X receptor alpha interferes with SREBP1c-mediated Abcd2 expression. Novel cross-talk in gene regulation.
The peroxisomal ATP binding cassette (ABC) transporter adrenoleukodystrophy-related protein, encoded by ABCD2, displays functional redundancy with the X-linked adrenoleukodystrophy-associated protein, making ABCD2 up-regulation of therapeutic value. Cholesterol lowering activates human ABCD2 in cultured cells. To investigate in vivo regulation by sterols, we first characterized a sterol regulatory element (SRE) in the murine Abcd2 promoter that is directly bound by SRE-binding proteins (SREBPs). Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation. Using fasting-refeeding and cholesterol loading, SREBP accessibility to the SRE/direct repeat 4 was tested. Results suggest that adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-regulated by concurrent activation of LXRalpha and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXRalpha. Finally, hepatic Abcd2 expression in LXRalpha,beta-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXRalpha as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXRalpha binding sites.
Weinhofer
Isabelle
I
Center for Brain Research, Medical University Vienna, A-1090 Vienna, Austria.
Kunze
Markus
M
Rampler
Heidelinde
H
Bookout
Angie L
AL
Forss-Petter
Sonja
S
Berger
Johannes
J
D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000273:Adipose Tissue / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D003084:Colestipol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009000:Monocytes / Q000378:metabolism; D016296:Mutagenesis; D009841:Oligonucleotides / Q000737:chemistry; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism* / Q000502:physiology; D013261:Sterols / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009841:Oligonucleotides; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D012313:RNA; D000255:Adenosine Triphosphate; D002784:Cholesterol; D008148:Lovastatin; D003084:Colestipol