Distinct modulatory roles for thyroid hormone receptors TRalpha and TRbeta in SREBP1-activated ABCD2 expression.
Adrenoleukodystrophy-related protein, a peroxisomal ABC transporter encoded by ABCD2, displays functional redundancy with the disease-associated X-linked adrenoleukodystrophy protein, making pharmacological induction of ABCD2 a potentially attractive therapeutic approach. Sterol regulatory element (SRE)-binding proteins (SREBPs) induce ABCD2 through an SRE overlapping with a direct repeat (DR-4) element. Here we show that thyroid hormone (T(3)) receptor (TR)alpha and TRbeta bind this motif thereby modulating SREBP1-dependent activation of ABCD2. Unliganded TRbeta, but not TRalpha, represses ABCD2 induction independently of DNA binding. However, activation by TRalpha and derepression of TRbeta are T(3)-dependent and require intact SRE/DR-4 motifs. Electrophoretic mobility shift assays with nuclear extracts support a direct interaction of TR and SREBP1 at the SRE/DR-4. In the liver, Abcd2 expression is high in young mice (with high T(3) and TRalpha levels) but downregulated in adults (with low T(3) and TRalpha but elevated TRbeta levels). This temporal repression of Abcd2 is blunted in TRbeta-deficient mice, and the response to manipulated T(3) states is abrogated in TRalpha-deficient mice. These findings show that TRalpha and TRbeta differentially modulate SREBP1-activated ABCD2 expression at overlapping SRE/DR-4 elements, suggesting a novel mode of cross-talk between TR and SREBP in gene regulation.
Weinhofer
Isabelle
I
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
Kunze
Markus
M
Rampler
Heidelinde
H
Forss-Petter
Sonja
S
Samarut
Jacques
J
Plateroti
Michelina
M
Berger
Johannes
J
D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D018776:Genes, erbA / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010957:Plasmids; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*; D013963:Thyroid Hormones / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection
C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones