Gueugnon F, Gondcaille C, Leclercq S, Bellenger J, Bellenger S, Narce M, Pineau T, Bonnetain F, Savary S
INSERM, U866, Universite de Bourgogne, 6, Bd Gabriel, Dijon, France.
Biochimie. 2007 Nov;89(11):1312-21. doi: 10.1016/j.biochi.2007.06.013. Epub 2007 Jul 6.
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC transporter, ALDP, supposed to participate in the transport of very long chain fatty acids (VLCFA). The adrenoleukodystrophy-related protein (ALDRP), which is encoded by the ABCD2 gene, is the closest homolog of ALDP and is considered as a potential therapeutic target since functional redundancy has been demonstrated between the two proteins. Pharmacological induction of Abcd2 by fibrates through the activation of PPARalpha has been demonstrated in rodent liver. DHEA, the most abundant steroid in human, is described as a PPARalpha activator and also as a prohormone able to mediate induction of several genes. Here, we explored the in vitro and in vivo effects of DHEA on the expression of peroxisomal ABC transporters. We show that Abcd2 and Abcd3 but not Abcd4 are induced in primary culture of rat hepatocytes by DHEA-S. We also demonstrate that Abcd2 and Abcd3 but not Abcd4 are inducible by an 11-day treatment with DHEA in the liver of male rodents but not in brain, testes and adrenals. Finally and contrary to Abcd3, we show that the mechanism of induction of Abcd2 is independent of PPARalpha.
X连锁肾上腺脑白质营养不良（X-ALD）是一种由ABCD1基因突变引起的神经退行性疾病，该基因编码一种过氧化物酶体ABC转运蛋白ALDP，推测其参与极长链脂肪酸（VLCFA）的转运。由ABCD2基因编码的肾上腺脑白质营养不良相关蛋白（ALDRP）是ALDP最接近的同源物，由于已证明这两种蛋白之间存在功能冗余，因此被视为潜在的治疗靶点。在啮齿动物肝脏中已证实贝特类药物通过激活PPARα可对Abcd2进行药理学诱导。脱氢表雄酮（DHEA）是人体内最丰富的类固醇，被描述为一种PPARα激活剂，也是一种能够介导多种基因诱导的前体激素。在此，我们探究了DHEA对过氧化物酶体ABC转运蛋白表达的体外和体内作用。我们发现，DHEA-S可在大鼠原代肝细胞培养物中诱导Abcd2和Abcd3的表达，但不能诱导Abcd4的表达。我们还证明，在雄性啮齿动物肝脏中，连续11天用DHEA处理可诱导Abcd2和Abcd3的表达，但在脑、睾丸和肾上腺中则不能。最后，与Abcd3相反，我们发现Abcd2的诱导机制独立于PPARα。
