Exogenous Addition of 25-Hydroxycholesterol Reduces Level of Very Long-Chain Fatty Acids in X-Linked Adrenoleukodystrophy

ChemistryOpen
Jiho JangKyung Hoon Min

Abstract

X-Linked adrenoleukodystrophy (X-ALD) is a severe metabolic disorder characterized by the accumulation of very long-chain fatty acids (VLCFAs). Recently, we demonstrated that levels of 25-hydroxycholesterol (25-HC) and cholesterol 25-hydroxylase (CH25H) were found to be elevated in X-ALD. Herein, we report that the exogenous addition of 25-HC significantly reduces C26:0 levels in X-ALD patient-derived fibroblasts and oligodendrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from X-ALD patients. Moreover, 25-HC treatment was found to down-regulate the expression of ELOVL1, a key enzyme for the synthesis of C26. In addition, activation of liver X receptor (LXR), a molecular target of endogenous 25-HC, also reduced C26:0 level. The reduction of C26:0 levels by 25-HC treatment might result, at least partially, from the decrease of ELOVL1 expression as well as the activation of LXR. Our findings could provide a better understanding of the role of 25-HC in X-ALD and useful information to find therapeutic agents to treat X-ALD.

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Citations

Nov 30, 2019·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Bela R TurkAnn B Moser
Jan 8, 2020·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Bela R TurkAnn B Moser

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Methods Mentioned

BETA
PCR
transfection

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Adrenoleukodystrophy

Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. Here is the latest research.