Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily D, Member 1
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ATP-Binding Cassette Transporters / genetics*
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ATP-Binding Cassette Transporters / metabolism
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Adrenoleukodystrophy / genetics
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Adrenoleukodystrophy / metabolism*
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Animals
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Cells, Cultured
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Cholesterol / blood
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Cholesterol / metabolism*
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Cholesterol / pharmacology
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Fatty Acids / metabolism*
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Fibroblasts / drug effects
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Gene Expression / drug effects
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Gene Expression Regulation*
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Humans
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Hydroxymethylglutaryl CoA Reductases / metabolism
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Liver / metabolism
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
Substances
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ABCD1 protein, human
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ATP Binding Cassette Transporter, Subfamily D, Member 1
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ATP-Binding Cassette Transporters
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Fatty Acids
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RNA, Messenger
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Cholesterol
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Hydroxymethylglutaryl CoA Reductases
Associated data
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GENBANK/BC011106
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GENBANK/MN008255