Document Detail

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.
MedLine Citation:
PMID:  21891797     Owner:  NLM     Status:  MEDLINE    
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.
Jaspreet Singh; Mushfiquddin Khan; Inderjit Singh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-04
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-17     Completed Date:  2012-02-02     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2056-69     Citation Subset:  IM    
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MeSH Terms
ATP-Binding Cassette Transporters / genetics,  metabolism
Acetylation / drug effects
Acetyltransferases / genetics
Adrenoleukodystrophy / genetics,  metabolism,  pathology*
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
Hydroxamic Acids / pharmacology*
Inflammation / metabolism
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
Reg. No./Substance:
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 Oxide Synthase Type II; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/fatty acid elongases; EC Deacetylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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