Characterization of the Adrenoleukodystrophy-Related (ALDR, ABCD2) Gene Promoter: Inductibility by Retinoic Acid and Forskolin

Pujol, Aurora; Troffer-Charlier, N.; Metzger, Elisabeth; Chimini, Giovanna; Mandel, Jean‐Louis

doi:10.1006/geno.2000.6367

Cited by 23 publications

(18 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A possible explanation could be that the strong synthetic LXR ligand T0901317 is expected to be more potent in inducing SREBP1c expression than dietary cholesterol treatment and thus might result in a titration of the positive and negative effect of SREBP1c and LXR␣, respectively, on the Abcd2 promoter. When wild type mice and LXR␣,␤-deficient mice were exposed to the RXR␣ ligand LG268, a strong induction of hepatic Abcd2 expression was observed, thus confirming previous studies demonstrating the inducibility of ABCD2 by 9-cis retinoic acid-activated RXR␣ in cultured cells (25). As activation of RXR␣ also results in stimulation of Abcd2 expression in the liver of LXR-deficient mice, a role for LXRs in this induction can be excluded.…”

Section: Discussionsupporting

confidence: 86%

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Weinhofer

Kunze

Rampler

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The peroxisomal ATP binding cassette (ABC) transporter adrenoleukodystrophy-related protein, encoded by ABCD2, displays functional redundancy with the X-linked adrenoleukodystrophyassociated protein, making ABCD2 up-regulation of therapeutic value. Cholesterol lowering activates human ABCD2 in cultured cells. To investigate in vivo regulation by sterols, we first characterized a sterol regulatory element (SRE) in the murine Abcd2 promoter that is directly bound by SRE-binding proteins (SREBPs). Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation. Using fasting-refeeding and cholesterol loading, SREBP accessibility to the SRE/direct repeat 4 was tested. Results suggest that adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-regulated by concurrent activation of LXR␣ and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXR␣. Finally, hepatic Abcd2 expression in LXR␣,␤-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXR␣ as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXR␣ binding sites. X-linked adrenoleukodystrophy (X-ALD2 ; OMIM 300100) is a neurodegenerative disorder caused by mutations in the ABCD1 (ALD) gene, encoding the peroxisomal ATP binding cassette (ABC) half-transporter adrenoleukodystrophy protein (ALDP) (1). Currently, no satisfying therapy is available for X-ALD patients.Next to ALDP, three additional mammalian peroxisomal ABC halftransporters have been identified: adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70), and PMP70-related protein (P70R), sharing 66, 39, and 25% amino acid identity with ALDP, respectively. Thus, the ABCD2-encoded ALDRP is the protein most closely related to ALDP and upon overexpression can functionally compensate for ALDP deficiency in X-ALD fibroblasts and Abcd1-deficient mice (2, 3). Therefore, pharmacological stimulation of ABCD2 expression has been targeted as an alternative therapeutic strategy for X-ALD (4), requiring detailed knowledge about how the ABCD2 gene is transcriptionally regulated.We recently showed that human ABCD2 is induced upon cholesterol depletion in cultured cells via a mechanism requiring the activation and binding of sterol regulatory element (SRE)-binding proteins (SREBPs) (5). SREBPs, which are synthesized as membrane-bound precursors and cleaved to generate the active nuclear form, are a class of transcription factors known to play a major role in regulating genes involved in fatty acid and cholesterol synthesis (reviewed in Ref. 6). To date, three SREBPs have been identified: SREBP1a and SREBP1c, which are produced from a single gene and preferentially regulate fatty acid synthesis, and SREBP2, encoded by a separate gene and controlling expression of ...

show abstract

Section: Discussionsupporting

confidence: 86%

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Weinhofer

Kunze

Rampler

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This finding, as well as our demonstration that the ABCD2 DRϩ4 can bind RXR␣/TR␤1 in vitro, suggests that the DRϩ4 motif might mediate the 9-cis-retinoic acid induction of ABCD2 observed in an embryonal carcinoma human cell line (Troffer-Charlier et al, 1998). Indeed, the 1.0-kb proximal region of the mouse or human ABCD2 promoter, which is also highly conserved in rat, has been shown to be sufficient to promote the 9-cisretinoic acid activation of a reporter gene cotransfected with RXR␣ (Pujol et al, 2000). Thus, retinoic acid would be likely to boost T 3 induction of ABCD2.…”

Section: Discussionmentioning

confidence: 84%

Thyroid Hormone Induction of the Adrenoleukodystrophy-Related Gene (ABCD2)

et al. 2003

View full text Add to dashboard Cite

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disorder associated with impaired very-long-chain fatty-acid (VL-CFA) ␤-oxidation caused by mutations in the ABCD1 (ALD) gene that encodes a peroxisomal membrane ABC transporter. ABCD2 (ALDR) displays partial functional redundancy because when overexpressed, it is able to correct the X-ALD biochemical phenotype. The ABCD2 promoter contains a putative thyroid hormone-response element conserved in rodents and humans. In this report, we demonstrate that the element is capable of binding retinoid X receptor and 3,5,3Ј-tri-iodothyronine (T 3 ) receptor (TR␤) as a heterodimer and mediating T 3 responsiveness of ABCD2 in its promoter context. After a T 3 treatment, an induction of the ABCD2 gene was observed in the liver of normal rats but not that of TR␤Ϫ/Ϫ mice. ABCD2 was not induced in the brain of the T 3 -treated rats. However, we report for the first time that induction of the ABCD2 redundant gene is feasible in myelin-producing cells (differentiated CG4 oligodendrocytes). The induction was specific for this cell type because it did not occur in astrocytes. Furthermore, we observed T 3 induction of ABCD2 in human and mouse ABCD1-deficient fibroblasts, which was correlated with normalization of the VLCFA ␤-oxidation. Finally, ABCD3 (PMP70), a close homolog of ABCD2, was also induced by T 3 in the liver of control rats, but not that of TR␤Ϫ/Ϫ mice, and in CG4 oligodendrocytes.

show abstract

“…Abcd2 is thus a prime therapeutic target [45][46][47][48]. These double mutant mice exhibited a more pronounced and earlier-onset axonal degenerative phenotype, manifesting at around 12 months of age, what makes them more suitable for therapeutic assays [18].…”

Section: Mouse Models For X-linked Adrenoleukodystrophy: Lessons Learntmentioning

confidence: 99%

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

Fourcade

Ferrer

Pujol

2015

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Peroxisomal and mitochondrial malfunction, which are highly intertwined through redox regulation, in combination with defective proteostasis, are hallmarks of the most prevalent multifactorial neurodegenerative diseases-including Alzheimer's (AD) and Parkinson's disease (PD)-and of the aging process, and are also found in inherited conditions. Here we review the interplay between oxidative stress and axonal degeneration, taking as groundwork recent findings on pathomechanisms of the peroxisomal neurometabolic disease adrenoleukodystrophy (X-ALD). We explore the impact of chronic redox imbalance caused by the excess of very long-chain fatty acids (VLCFA) on mitochondrial respiration and biogenesis, and discuss how this impairs protein quality control mechanisms essential for neural cell survival, such as the proteasome and autophagy systems. As consequence, prime molecular targets in the pathogenetic cascade emerge, such as the SIRT1/PGC-1α axis of mitochondrial biogenesis, and the inhibitor of autophagy mTOR. Thus, we propose that mitochondria-targeted antioxidants; mitochondrial biogenesis boosters such as the antidiabetic pioglitazone and the SIRT1 ligand resveratrol; and the autophagy activator temsirolimus, a derivative of the mTOR inhibitor rapamycin, hold promise as disease-modifying therapies for X-ALD.

show abstract

Characterization of the Adrenoleukodystrophy-Related (ALDR, ABCD2) Gene Promoter: Inductibility by Retinoic Acid and Forskolin

Cited by 23 publications

References 39 publications

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Thyroid Hormone Induction of the Adrenoleukodystrophy-Related Gene (ABCD2)

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

Contact Info

Product

Resources

About