Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy

Singh, Jaspreet; Khan, Mushfiquddin; Singh, Inderjit

doi:10.1194/jlr.m800321-jlr200

Cited by 63 publications

(115 citation statements)

References 68 publications

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“…Other peroxisomal disorders are also associated with an increase in VLC-FA and VLC-PUFA in brain and plasma (69)(70)(71)(72)(73)(74)(75)(76)(77). Postmortem analyses of 4 day-to 5 monthold whole brains of Zellweger patients showed higher concentrations of VLC-PUFA than those found in normal brains ( 16 ).…”

Section: Nomenclature and Structure Of Vlc-fa And Vlc-pufamentioning

confidence: 99%

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Agbaga

Mandal

Anderson

2010

Journal of Lipid Research

146

147

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This article is available online at http://www.jlr.org tively rare compared with the abundance of FA containing 16-22 carbons, they are widely distributed in higher plants and animals ( 1-10 ). They are found in most living organisms from humans to autotrophic and heterotrophic lower organisms, including microalgae, sponges, bacteria, and fungi ( 1,9,(11)(12)(13)(14)(15). VLC-FA are found mainly in seed oils, plant waxes, cutin, suberin, skin, hair, and wax glands ( 1 ), whereas VLC-PUFA are found primarily in retina, brain ( 1, 16 ), testis, and spermatozoa ( 17-19 ).The unusually long hydrocarbon chains with 3 -9 double bonds, which are prone to oxidative damage, combined with the small quantities found in mammalian tissues, have made them diffi cult to isolate and analyze in detail over the years ( 9 ). Very little is therefore known about the metabolism and function of VLC-PUFA and VLC-FA in mammals, except for their increase in disorders of peroxisomal function ( 3,16,20,21 ), as components of the secretions of meibomian glands (22)(23)(24)(25)(26)(27), and their reduction in animal models of autosomal dominant Stargardt-like macular dystrophy (STGD3) ( 28-32 ), a juvenile form of macular degeneration. In contrast, the roles of long-chain PUFA (LC-PUFA) with carbon chains that range from C18 to C24 are fairly well understood, especially in the retina and other neural tissues. A detailed account on the role and function of LC-PUFA in the retina was reviewed earlier (33)(34)(35)(36).Recent interest in the molecular and physiological roles of VLC-PUFA in the retina came from the fi nding that the gene associated with STGD3 shared sequence homologies with genes involved in FA elongation ( 37,38 ) Abbreviations: AOX, acyl-CoA oxidase; DHA or 22:6n3, docosahexaenoic acid; ELOVL, elongation of very long-chain FA; ELOVL4, elongation of very long-chain FA-4; ERG, electroretinogram; LC-PUFA, long-chain PUFA; PC, phosphatidylcholine; ROS, retinal outer segments; RPE, retinal pigment epithelium; STGD1, recessive Stargardt degeneration; STGD3, autosomal dominant Stargardt-like macular dystrophy; VLC-FA, very long-chain saturated or monounsaturated FA; VLC-PUFA, very long-chain PUFA.

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Section: Nomenclature and Structure Of Vlc-fa And Vlc-pufamentioning

confidence: 99%

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Agbaga

Mandal

Anderson

2010

Journal of Lipid Research

146

147

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“…The Silencer siRNA (Ambion; Austin, TX) was used for Abcd1 and Abcd2 silencing in primary mouse astrocytes as described previously ( 19 ). The siRNAs were mixed and diluted in OPTI-MEM1 medium to a fi nal concentration of 30 nM/well.…”

Section: Lipid Extraction and Fa Analysismentioning

confidence: 99%

“…The peroxisomal oxidation of FAs in control, X-ALD fibroblasts, and SAHA-treated X-ALD fi broblasts was determined in 6-well plates as described previously ( 19 ). ␤ -Oxidation of FAs to acetate (water-soluble product) was determined using [1-14 C]-labeled FAs as substrate (C 24:0 , lignoceric acid, or C 16:0 , palmitic acid) (American Radiolabeled Co. ; St. Louis, MO), as described previously ( 52 ).…”

Section: Fa ␤ -Oxidationmentioning

confidence: 99%

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

Singh

Khan

Singh

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words peroxisome • very long chain FA • glia • nitric oxide • cytokine • suberoylanilide hydroxamic acid • X-adrenoleukodystrophy X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 ( 1, 2 ). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis ( 3-5 ). The biochemical signature of X-ALD is increased levels of saturated straight-chain very long chain FAs (VLCFAs; >22:0). VLCFA accumulates in all tissues and lipid classes; however, the degree of accumulation is higher in the cholesterol ester and sphingolipid fractions of brain white matter and adrenal cortex ( 6 ). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present. However, the VLCFA, especially C26:0, has been documented to cause metabolic alterations leading to membrane perturbation, redox imbalance ( 13 ), and changes in membrane lipid composition ( 14-18 ), as well as the induction of infl ammatory mediators in cultured astrocytes ( 19 ). This study was supported in part by grants from the National Institutes of Health (Grants NS-22576, NS-37766, C06 RR-018823, and C06 RR-015455, and VA merit award BX1072-01. Its Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; BBB, blood-brain barrier; cALD, cerebral adrenoleukodystrophy; FAME, FA methyl ester; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; 5-LOX, 5-lipoxygenase; PA, phenylacetate; PBA, phenylbutyrate; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TNF-␣ , tumor necrosis factor-␣ ; X-ALD, X-adrenoleukodystrophy; VLCFA, very long chain FA.

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“…Recently, Singh et al showed that silencing of the Abcd2 gene decreased the ratio of the C24:0/C16:0 β-oxidation activity, as the silencing of the Abcd1 gene had done, in mouse primary astrocytes. 32) Fourcade et al demonstrated that C26:0 β-oxidation activity in the cortical brain slices of Abcd2-deficient mice decreased to approximately 70% of the control. 31) It is thus possible that Abcd2 contributes to the abcd1-independent pathway in the case of mouse astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

Morita

Shinbo

Asahi

et al. 2012

Biological & Pharmaceutical Bulletin

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Very long chain fatty acid (VLCFA) metabolism in astrocytes is important for the maintenance of myelin structure in central nervous system. To analyze the contribution of the ABCD1-dependent and -independent pathways to VLCFA metabolism in astrocytes, we prepared human glioblastoma U87 cells with a silencing of ABCD1 and primary astrocytes from abcd1-deficient mice, and measured fatty acid β-oxidation in the presence or absence of a potent inhibitor of carnitine palmitoyltransferase I, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In U87 cells, C24:0 β-oxidation was decreased to ca. 70% of the control in the presence of POCA, and the activity was further decreased to ca. 20% by the silencing of ABCD1. In mouse primary astrocytes, C24:0 β-oxidation was also decreased to ca. 70% of the control in the presence of POCA. The C24:0 β-oxidation in Abcd1-deficient primary astrocytes was ca. 60% of the wild-type cells and the activity was further decreased to ca. 25% in the presence of POCA. Compared to human skin fibroblasts, in which VLCFA β-oxidation is not significantly inhibited by POCA, approximately one-third of the overall VLCFA β-oxidation was inhibited in both types of astrocytic cells. These results suggest that VLCFA is indeed β-oxidized in ABCD1-dependent pathway, but the ABCD1-independent peroxisomal and mitochondrial β-oxidation pathways significantly contribute to VLCFA β-oxidation in astrocytic cells.Key words very long chain fatty acid β-oxidation; astrocyte; ABCD1; peroxisome; mitochondria Peroxisomes are single membrane organelles that are present in almost all eukaryotic cells. The peroxisomes are involved in a variety of metabolic processes, including the β-oxidation of fatty acids, especially very long chain fatty acids (VLCFA, >C22), and the synthesis of ether phospholipids and bile acids in mammals.1) Transport of substrates for fatty acid β-oxidation across the peroxisomal membrane is an essential step in this metabolism. Peroxisomal ATP-binding cassette (ABC) proteins have been implicated in this transport.To date, three ABC proteins, classified into "subfamily D," have been identified in mammalian peroxisomes. These are adrenoleukodystrophy protein (ALDP/ABCD1),2) ALDP-related protein (ALDRP/ABCD2) 3) and a 70-kDa peroxisomal membrane protein (PMP70/ABCD3). 4) Dysfunction of ABCD1 causes the human genetic disorder X-linked adrenoleukodystrophy (X-ALD) characterized by an accumulation of VLCFA because of the impaired peroxisomal β-oxidation of VLCFA.5) VLCFA β-oxidation in X-ALD patient fibroblasts was restored by the expression of ABCD1. Likewise, the expression of ABCD2, which has a high sequence similarity to ABCD1, also restored VLCFA β-oxidation in X-ALD fibro blasts.6) In analogy to the role of Pxa1p/Pxa2p, 7) yeast peroxisomal half-ABC transporters, which is involved in the transport of acyl-CoA, ABCD1 and ABCD2 are thought to be involved in the metabolic transport of VLCFA-CoA. 8,9) ABCD3 is suggested to be involved in the metabolic transport of long chain fatty acids (LCFA)...

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Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy

Cited by 63 publications

References 68 publications

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

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

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

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