Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy

Khan, Mushfiquddin; Singh, Jaspreet; Gilg, Anne G.; Uto, Takuhiro; Singh, Inderjit

doi:10.1194/jlr.m002329

Cited by 38 publications

(43 citation statements)

References 41 publications

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“…SAHA treatment of Abcd1/2-silenced mouse astrocytes reduced the expressions of iNOS and TNF-␣ (mRNA and protein), suppressed NF-B activation, and reduced ROS production. The observed increased activation of lipoxidative enzymes in X-ALD brain ( 18 ) and in Abcd1/2-silenced astrocytes ( 19 ) suggests the role of these proinfl ammatory mediators in the pathobiology of X-ALD. SAHA treatment also reduced the activation of 5-LOX in Abcd1/2-silenced mouse astrocytes.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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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“…103 Interestingly, it has recently been shown that this lipotoxic effect of VLCFA accumulation is mediated through 5-LOX activity and enhanced production of the pro-inflammatory cysteinyl leukotrienes (CysLTs) and leukotriene B4 (LTB 4 ). 104 It is therefore plausible that the substantial downregulation of Abcd2 during acute SCI may contribute to a similar VLCFA-mediated lipotoxic effect, thus exacerbating inflammation and secondary damage in the days following injury. Developing an understanding of the multifaceted contributions of ABC transporter family members to SCI pathophysiology remains an ongoing topic of investigation in our laboratory.…”

Section: Dulin Et Almentioning

confidence: 99%

The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord

Dulin¹,

Moore²,

Grill³

2013

Journal of Neurotrauma

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There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male SpragueDawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.

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“…Il en est de même de l'augmentation du taux de la sous-unité membranaire de la NADPH oxydase gp91 PHOX dans les leucocytes de patients [22] et de la présence de protéines carbonylées dans les monocytes [23]. Au niveau des lésions cérébrales plusieurs anomalies ont été décrites : l'augmentation importante des transcrits de cytokines pro-inflammatoires et de NO synthase [24], celle du niveau d'expression de la 5-lipoxygénase [25] et la présence d'infiltrats périvasculaires de lymphocytes T et B et de macrophages. Une analyse fonctionnelle géno-mique par puce à ADN réalisée à partir d'échantillons de cerveaux de patients CCALD et AMN a également révélé des désordres métaboliques : insulino-résistance et anomalies de la glycolyse.…”

Section: Les Transporteurs Abc De La Membrane Peroxysomaleunclassified

“…Les souris déficientes en ABCD1 expriment d'ailleurs des perturbations métaboliques analogues à celles qui sont observées chez l'homme, ainsi qu'un stress oxydant important [26]. L'inactivation d'ABCD1 dans des astrocytes à l'aide de siARN démontre l'implication d'ABCD1 dans le contrôle de l'équilibre Redox et de l'inflammation [25,27]. Bien que la déficience en ABCD1 et l'implication des AGTLC aient été démontrées dans la géné-ration d'un stress oxydant dans des oligodendrocytes [28], cela n'exclut pas que d'autres facteurs puissent moduler ce phénomène in vivo et contribuer ainsi au déclenchement de la forme sévère d'X-ALD.…”

Section: Les Transporteurs Abc De La Membrane Peroxysomaleunclassified

Transporteurs ABC peroxysomaux et adrénoleucodystrophie liée au chromosome X

Geillon

Trompier²,

Gondcaille³

et al. 2012

Med Sci (Paris)

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Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy

Cited by 38 publications

References 41 publications

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

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

The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord

Transporteurs ABC peroxysomaux et adrénoleucodystrophie liée au chromosome X

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