Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator.
X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARalpha-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARalpha independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition.
Gondcaille
Catherine
C
Laboratoire de Biologie Moléculaire et Cellulaire, Faculté des Sciences Gabriel, 21000 Dijon, France.
Depreter
Marianne
M
Fourcade
Stéphane
S
Lecca
Maria Rita
MR
Leclercq
Sabrina
S
Martin
Pascal G P
PG
Pineau
Thierry
T
Cadepond
Françoise
F
ElEtr
Martine
M
Bertrand
Nathalie
N
Beley
Alain
A
Duclos
Sandrine
S
De Craemer
Dirk
D
Roels
Frank
F
Savary
Stéphane
S
Bugaut
Maurice
M
D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005347:Fibroblasts; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000648:ultrastructure; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D010654:Phenylbutyrates / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D006655:Histone Deacetylases