| Histone deacetylase inhibitor suberoylanilide hydroxamic acid normalizes the levels of very long chain fatty acids in human skin fibroblasts from X-Adrenoleukodystrophy patients and downregulates the expression of proinflammatory cytokines in Abcd1/2 silenced mouse astrocytes. | |
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MedLine Citation:
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PMID: 21891797 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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X-Adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder, caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal β-oxidation of very long chain fatty acids (VLCFA>C22:0) and the resultant pathognomic accumulation of VLCFA. The accumulation of VLCFA leads to a neuroinflammatory disease process associated with demyelination of the cerebral white matter. The present study underlines the importance of a potent histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in inducing the expression of ABCD2 (ALDRP), and normalizing the peroxisomal β-oxidation as well as the saturated and monounsaturated VLCFAs in cultured human skin fibroblasts of X-ALD patients. The expression of ELOVL1, the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1), was also reduced by SAHA treatment. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes we examined the effects of SAHA in VLCFA-induced inflammatory response. SAHA treatment decreased the inflammatory response as expression of inducible nitric oxide synthase, inflammatory cytokine, and activation of NF-κB in Abcd1/Abcd2-silenced mouse primary astrocytes was reduced. These observations indicate that SAHA corrects both the metabolic disease of VLCFA as well as the secondary inflammatory disease; therefore, it may be an ideal drug candidate to be tested for X-ALD therapy in humans. |
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Authors:
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Jaspreet Singh; Mushfiqqudin Khan; Inderjit Singh |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-4 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Medical University of South Carolina, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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