Hama Kotaro, Fujiwara Yuko, Morita Masashi, Yamazaki Fumiyoshi, Nakashima Yuko, Takei Shiro, Takashima Shigeo, Setou Mitsutoshi, Shimozawa Nobuyuki, Imanaka Tsuneo, Yokoyama Kazuaki
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
Department of Biological Chemistry, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Lipids. 2018 Jan;53(1):85-102. doi: 10.1002/lipd.12022. Epub 2018 Feb 22.
ABCD1 is a gene responsible for X-linked adrenoleukodystrophy (X-ALD), and is critical for the transport of very long-chain fatty acids (VLCFA) into peroxisomes and subsequent β-oxidation. VLCFA-containing lipids accumulate in X-ALD patients, although the effect of ABCD1-deficiency on each lipid species in the central nervous system has not been fully characterized. In this study, each phospholipid and lysophospholipid species in Abcd1-deficient mice brains were profiled by liquid chromatography-mass spectrometry. Among the phospholipid and lysophospholipid species that are significantly more enriched in Abcd1-deficient mice brains, VLCFA were present in 75, 15, 5, 4, and 1 species of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, and lysophosphatidylethanolamine, respectively. Most VLCFA were incorporated at the sn-1 position of phosphatidylcholine and phosphatidylethanolamine. Among the phospholipid species that are significantly less enriched in Abcd1-deficient mice brains, odd-numbered saturated or mono-unsaturated fatty acyl moieties are contained in all phosphatidylcholine species. In addition, a number of phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine species contained highly unsaturated fatty acyl moieties. Intriguingly, 44:1 phosphatidylcholine with VLCFA was mainly distributed in the gray matter, such as the cortex, but not in the white matter in the cerebrum and cerebellum. These results show that ABCD1-deficiency causes metabolic alternation of long-chain fatty acids and VLCFA. Moreover, our results imply a molecular mechanism for the incorporation of saturated or monounsaturated VLCFA into the sn-1 position of phospholipids, and also indicate that the distribution of phospholipids with VLCFA may correlate with the development of X-ALD.
ABCD1是一种与X连锁肾上腺脑白质营养不良（X-ALD）相关的基因，对于超长链脂肪酸（VLCFA）转运到过氧化物酶体以及随后的β氧化过程至关重要。尽管ABCD1缺乏对中枢神经系统中每种脂质种类的影响尚未完全明确，但含VLCFA的脂质会在X-ALD患者体内蓄积。在本研究中，通过液相色谱-质谱联用技术对Abcd1基因缺陷小鼠大脑中的每种磷脂和溶血磷脂种类进行了分析。在Abcd1基因缺陷小鼠大脑中显著富集的磷脂和溶血磷脂种类中，VLCFA分别存在于75种、15种、5种、4种和1种的磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、溶血磷脂酰胆碱和溶血磷脂酰乙醇胺中。大多数VLCFA掺入到磷脂酰胆碱和磷脂酰乙醇胺的sn-1位。在Abcd1基因缺陷小鼠大脑中显著减少的磷脂种类中，所有磷脂酰胆碱种类都含有奇数碳饱和或单不饱和脂肪酰基部分。此外，许多磷脂酰甘油、磷脂酰肌醇和磷脂酰丝氨酸种类含有高度不饱和脂肪酰基部分。有趣的是，含VLCFA的44:1磷脂酰胆碱主要分布在灰质中，如大脑皮层，但在大脑和小脑的白质中不存在。这些结果表明，ABCD1缺乏会导致长链脂肪酸和VLCFA的代谢改变。此外，我们的结果暗示了饱和或单不饱和VLCFA掺入磷脂sn-1位的分子机制，并且还表明含VLCFA的磷脂分布可能与X-ALD的发展相关。
