Weinhofer Isabelle, Forss-Petter Sonja, Kunze Markus, Zigman Mihaela, Berger Johannes
Center for Brain Research, Medical University Vienna, Austria.
FEBS Lett. 2005 Oct 24;579(25):5512-6. doi: 10.1016/j.febslet.2005.09.014. Epub 2005 Sep 27.
The neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is caused by ABCD1 mutations and characterized by very long-chain fatty acid (VLCFA) accumulation. Cholesterol-lowering normalized VLCFA in fibroblasts and plasma of X-ALD patients. We show that in cultured cells, cholesterol-loading induces ABCD1. In X-ALD mice, plasma cholesterol is elevated and not further increasable by cholesterol-feeding, whereas hepatic HMG-CoA reductase and Abcd2 are downregulated. Upon cholesterol modulation, brain VLCFA increased in X-ALD mice, but decreased in controls. In murine X-ALD fibroblasts, cholesterol-lowering did not normalize VLCFA. Thus, ALDP-deficiency and VLCFA are linked to cholesterol but species differences complicate evaluating cholesterol-lowering drugs in X-ALD mice.
X连锁肾上腺脑白质营养不良（X-ALD）是一种神经退行性疾病，由ABCD1基因突变引起，其特征是极长链脂肪酸（VLCFA）蓄积。降低胆固醇可使X-ALD患者成纤维细胞和血浆中的VLCFA恢复正常。我们发现，在培养细胞中，胆固醇负载可诱导ABCD1。在X-ALD小鼠中，血浆胆固醇升高，喂食胆固醇后不再进一步升高，而肝脏HMG-CoA还原酶和Abcd2下调。在调节胆固醇后，X-ALD小鼠脑内VLCFA增加，而对照组则减少。在小鼠X-ALD成纤维细胞中，降低胆固醇并不能使VLCFA恢复正常。因此，ALDP缺乏和VLCFA与胆固醇有关，但物种差异使评估X-ALD小鼠中的降胆固醇药物变得复杂。
