| HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD 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: MEDLINE |
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 FAs (VLCFAs >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 [adrenoleukodystrophy-related protein (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 catalyzing the synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1), was also reduced by SAHA treatment. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes, we also 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 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; Mushfiquddin Khan; Inderjit Singh |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-09-04 |
Journal Detail:
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Title: Journal of lipid research Volume: 52 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-10-17 Completed Date: 2012-02-02 Revised Date: 2013-02-19 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 2056-69 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA. singhi@musc.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
/
genetics,
metabolism Acetylation / drug effects Acetyltransferases / genetics Adrenoleukodystrophy / genetics, metabolism, pathology* Animals Astrocytes / drug effects*, metabolism Blood-Brain Barrier / drug effects, metabolism Cytokines / genetics* Down-Regulation / drug effects Fatty Acids / chemistry, metabolism* Fibroblasts / cytology, drug effects*, metabolism, pathology Gene Silencing* Histone Deacetylase Inhibitors / pharmacology Histone Deacetylases / metabolism Humans Hydroxamic Acids / pharmacology* Inflammation / metabolism Mice Nitric Oxide Synthase Type II / genetics Oxidation-Reduction / drug effects Oxidative Stress / drug effects Peroxisomes / drug effects, metabolism RNA, Messenger / genetics, metabolism Skin / pathology |
| Grant Support | |
ID/Acronym/Agency:
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C06 RR-015455/RR/NCRR NIH HHS; C06 RR-018823/RR/NCRR NIH HHS; NS-22576/NS/NINDS NIH HHS; NS-37766/NS/NINDS NIH HHS; R01 NS022576-27/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCD2 protein, mouse; 0/ABCD3 protein, human; 0/Abcd1 protein, mouse; 0/Cytokines; 0/Fatty Acids; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/RNA, Messenger; 149647-78-9/vorinostat; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/fatty acid elongases; EC 3.5.1.98/Histone Deacetylases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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