|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.|
|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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|Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-09-04|
|Title: Journal of lipid research Volume: 52 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2011 Nov|
|Created Date: 2011-10-17 Completed Date: 2012-02-02 Revised Date: 2014-09-13|
Medline Journal Info:
|Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States|
|Languages: eng Pagination: 2056-69 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
ATP-Binding Cassette Transporters
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
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
|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/NS/NINDS NIH HHS; R01 NS022576-27/NS/NINDS NIH HHS|
|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 18.104.22.168/Nitric Oxide Synthase Type II; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/fatty acid elongases; EC 22.214.171.124/Histone Deacetylases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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