Rampler Heidelinde, Weinhofer Isabelle, Netik Angela, Forss-Petter Sonja, Brown Peter J, Oplinger Jeffrey A, Bugaut Maurice, Berger Johannes
Brain Research Institute, University of Vienna, Vienna, Austria.
Mol Genet Metab. 2003 Dec;80(4):398-407. doi: 10.1016/j.ymgme.2003.09.002.
Adrenoleukodystrophy protein (ABCD1), a peroxisomal membrane protein, is mutated in patients affected by X-linked adrenoleukodystrophy (X-ALD). Adrenoleukodystrophy-related protein (ABCD2) is the closest relative of ABCD1. Pharmacological induction of ABCD2 gene expression has been proposed as a novel therapy strategy for X-ALD. Fibrates induce peroxisome proliferation and Abcd2 expression in rodent liver. Here we evaluate the possibility of using peroxisome proliferator-activated receptor alpha (PPARalpha) agonists for pharmacological induction of ABCD2 expression. In the liver of PPARalpha-deficient mice, both the constitutive and the fenofibrate-inducible Abcd2 gene expression was found to be PPARalpha-dependent. In the brain, PPARalpha-deficiency has no effect on Abcd2 expression. In mice orally treated with the novel, highly selective, and potent PPARalpha agonists GW 7647, GW 6867, and tetradecylthioacetic acid, Abcd2 expression was induced in liver and adrenal glands, but not in brain and testis. None of four putative PPREs identified in the 5(')-flanking DNA and in intron 1 of the Abcd2 gene conferred fibrate response in luciferase reporter assays. Thus, although fibrate-mediated Abcd2 induction is PPARalpha-dependent, it appears to be an indirect mechanism. Within the mouse Abcd2 promoter, a putative sterol regulatory element (SRE) similar in sequence and position to the characterized SRE sequence of the human ABCD2 promoter, was identified. A PPARalpha dependent induction of the sterol regulatory-binding protein 2 (SREBP2) and a down-regulation of SREBP1c mRNA levels could be demonstrated after fenofibrate treatment of mice. Our results suggest that the PPARalpha agonist-mediated induction of Abcd2 expression seems to be indirect and possibly mediated by SREBP2.
肾上腺脑白质营养不良蛋白（ABCD1）是一种过氧化物酶体膜蛋白，在患有X连锁肾上腺脑白质营养不良（X-ALD）的患者中发生突变。肾上腺脑白质营养不良相关蛋白（ABCD2）是ABCD1的近亲。已提出药物诱导ABCD2基因表达作为X-ALD的一种新治疗策略。贝特类药物可诱导啮齿动物肝脏中的过氧化物酶体增殖和Abcd2表达。在此，我们评估使用过氧化物酶体增殖物激活受体α（PPARα）激动剂进行药物诱导ABCD2表达的可能性。在PPARα缺陷小鼠的肝脏中，发现组成型和非诺贝特诱导型Abcd2基因表达均依赖于PPARα。在大脑中，PPARα缺陷对Abcd2表达没有影响。在用新型、高度选择性和强效的PPARα激动剂GW 7647、GW 6867和十四烷基硫代乙酸口服治疗的小鼠中，肝脏和肾上腺中诱导了Abcd2表达，但大脑和睾丸中未诱导。在荧光素酶报告基因测定中，在Abcd2基因的5′侧翼DNA和内含子1中鉴定出的四个假定的PPREs均未赋予贝特类药物反应。因此，尽管贝特类药物介导的Abcd2诱导依赖于PPARα，但似乎是一种间接机制。在小鼠Abcd2启动子内，鉴定出一个假定的甾醇调节元件（SRE），其序列和位置与人类ABCD2启动子的特征性SRE序列相似。非诺贝特治疗小鼠后，可证明甾醇调节结合蛋白2（SREBP2）的PPARα依赖性诱导和SREBP1c mRNA水平的下调。我们的结果表明，PPARα激动剂介导的Abcd2表达诱导似乎是间接的，可能由SREBP2介导。
