A key role for the peroxisomal<i>ABCD2</i>transporter in fatty acid homeostasis

Fourcade, Stéphane; Ruíz, Montserrat; Camps, Carme; Schlüter, Agatha; Houten, Sander M.; Mooyer, Petra; Pàmpols, T; Dacremont, Georges; Wanders, Ronald J. A.; Girós, M.; Pujol, Aurora

doi:10.1152/ajpendo.90736.2008

Cited by 87 publications

(90 citation statements)

References 67 publications

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“…Moreover, we found an inverse correlation between the expression level of ALDRP-EGFP and the fatty acid content in PL of VLCFA (C26:0, C24:0, C26:1, and C24:1). These findings are consistent with the observed accumulation of C26:0 and C24:0 in tissues rich in ALDRP in Abcd2 null mice (19,29). Altogether, these results suggest a role of ALDRP in the transport of these fatty acids and are in agreement with the recognized partial functional redundancy between ALDP and ALDRP toward these substrates.…”

Section: Discussionsupporting

confidence: 91%

“…The putative role of ALDRP toward these fatty acids has been suggested from the observed accumulation of such fatty acids in specific tissues (adrenals and sciatic nerve) of Abcd2 null mice (19). In our experiments, we could not evidence any changes in the content of these fatty acids.…”

Section: Discussioncontrasting

confidence: 47%

“…ALDRP has been suggested to play a role in the transport of other saturated and monounsaturated fatty acids such as C20:0, C22:0, and C22:1 (19). The putative role of ALDRP toward these fatty acids has been suggested from the observed accumulation of such fatty acids in specific tissues (adrenals and sciatic nerve) of Abcd2 null mice (19).…”

Section: Discussionmentioning

confidence: 99%

“…Concerning the substrates, an overlap in the substrate specificity of ALDP, ALDRP, and PMP70 is likely. Nevertheless, lessons from the different knockout mice models suggest that PMP70 would preferentially be dedicated to the transport of branched-chain fatty acids and bile acid precursors (18), whereas ALDRP would play a role in the catabolism of long-chain saturated and monounsaturated fatty acids and in the synthesis of DHA (C22:6n-3) (19). However, the exact nature of the substrates transported by ALDRP and PMP70, their relationship with ALDP, and their state of dimerization (homo-or heterodimerization) absolutely needs further investigations particularly in situations of induced overexpression, a situation found in pharmacological induction based therapies.…”

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confidence: 99%

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Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Génin

Geillon

Gondcaille

et al. 2011

Journal of Biological Chemistry

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X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP. ALDP is supposed to function as a homodimer allowing the entry of CoA-esters of very-long chain fatty acids (VLCFA) into the peroxisome, the unique site of their ␤-oxidation. ALDP deficiency can be corrected by overexpression of ALDRP, its closest homolog. However, the exact nature of the substrates transported by ALDRP and its relationships with ALDP still remain unclear. To gain insight into the function of ALDRP, we used cell models allowing the induction in a dose-dependent manner of a wild type or a mutated non-functional ALDRP-EGFP fusion protein. We explored the consequences of the changes of ALDRP expression levels on the fatty acid content (saturated, monounsaturated, and polyunsaturated fatty acids) in phospholipids as well as on the levels of ␤-oxidation of 3 suspected substrates: C26:0, C24:0, and C22:6n-3 (DHA). We found an inverse correlation between the fatty acid content of saturated (C26:0, C24:0) and monounsaturated (C26:1, C24:1) VLCFA and the expression level of ALDRP. Interestingly, we obtained a transdominant-negative effect of the inactive ALDRP-EGFP on ALDP function. This effect is due to a physical interaction between ALDRP and ALDP that we evidenced by proximity ligation assays and coimmunoprecipitation. Finally, the ␤-oxidation assays demonstrate a role of ALDRP in the metabolism of saturated VLCFA (redundant with that of ALDP) but also a specific involvement of ALDRP in the metabolism of DHA. X-linked adrenoleukodystrophy (X-ALD)2 (OMIM 300100) is a very complex neurodegenerative disorder whose physiopathogenesis remains to be clarified (1). X-ALD is caused by mutations in the ABCD1 gene located in Xq28, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP (adrenoleukodystrophy-protein) (2). This protein has the structure of a half ABC transporter, which is supposed to function as a homodimer (3, 4). However, heterodimerization with one of the other members of the ABCD subfamily (i.e. ALDRP (encoded by the ABCD2 gene (5)), PMP70 (ABCD3 (6)), and PMP69 (ABCD4 (7, 8)) cannot be excluded especially in the situation where these proteins are overexpressed. Although a mirror expression pattern is often observed between ALDP and ALDRP when specific cell types are analyzed (9), peroxisomal ABC transporters have overlapping expression patterns rendering possible such interactions (5, 10). Coimmunoprecipitation experiments or FRET analysis have demonstrated heterodimerization in cells overexpressing the peroxisomal ABC transporters (11,12). Although the peroxisomal localization of ALDP, ALDRP, and PMP70 is clearly demonstrated, PMP69 has recently been described to be localized in the endoplasmic reticulum and was found to be absent in the peroxisome. This excludes a possible interaction at the peroxisomal membrane with the other ABC...

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Génin

Geillon

Gondcaille

et al. 2011

Journal of Biological Chemistry

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“…19,67 It is worth mentioning that to date, no disease-causative role for ABCD2 has been found, although its absence provokes a partially overlapping fatty acid pattern when compared with the ABCD1-dependent biochemical phenotype. 68,69 We assessed the clinical signs of AMN in these double Abcd1 − / Abcd2 −/− mice. The mice used for the study were of a pure C57BL/6 J background.…”

Section: Discussionmentioning

confidence: 99%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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Antioxidants halt axonal degeneration in a mouse model of X‐adrenoleukodystrophy

López-Erauskin

Fourcade

Galino

et al. 2011

Annals of Neurology

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124

139

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ObjectiveAxonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).MethodsX-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.ResultsHere, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.InterpretationWe have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. Ann Neurol 2011;

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A key role for the peroxisomalABCD2transporter in fatty acid homeostasis

Cited by 87 publications

References 67 publications

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Antioxidants halt axonal degeneration in a mouse model of X‐adrenoleukodystrophy

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