Evaluation of the therapeutic potential of PPARα agonists for X-linked adrenoleukodystrophy

Rampler, Heidelinde; Weinhofer, Isabelle; Netik, Angela; Forss‐Petter, Sonja; Brown, Peter J.; Oplinger, Jeffrey A.; Bugaut, Maurice; Berger, Johannes

doi:10.1016/j.ymgme.2003.09.002

Cited by 23 publications

(22 citation statements)

References 30 publications

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“…3c). Thus, in accordance with our previous studies involving synthetic PPAR␣ agonists (20,24), hepatic Abcd2 regulation correlated with a PPAR␣ and not with a SREBP1c target gene, although several investigations failed to …”

Section: A Functional Sre Is Present In the Murine Abcd2 Promoter Thasupporting

confidence: 91%

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Weinhofer

Kunze

Rampler

et al. 2005

Journal of Biological Chemistry

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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 ...

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Section: A Functional Sre Is Present In the Murine Abcd2 Promoter Thasupporting

confidence: 91%

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Weinhofer

Kunze

Rampler

et al. 2005

Journal of Biological Chemistry

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“…However, its expression is induced by fasting, feeding fi brates, and statin treatment, while expression levels in brain remain constant (13)(14)(15)(16)(17). More recently, D2 mRNA was shown to be expressed in adipose tissue where its mRNA levels are highest in the fed state, decline in the fasted state, and return during refeeding ( 17 ).…”

Section: Cell Culturementioning

confidence: 99%

ABCD2 is abundant in adipose tissue and opposes the accumulation of dietary erucic acid (C22:1) in fat

Liu¹,

Sabeva²,

Bhatnagar

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.orgPeroxisomes play essential roles in the metabolism of both dietary and endogenously synthesized lipids ( 1, 2 ). The synthesis of the etherphospholipids (platelet activating factor and plasmalogens), partial ␤ -oxidation of verylong-chain fatty acids (VLCFAs; C>22), and the ␣ -oxidation of phytanic acid occur within this organelle. A comprehensive integrative map of peroxisomal metabolic pathways can be found at www.peroxisomedb.org ( 3 ). The importance of the organelle is best exemplifi ed by the occur rence of peroxisome biogenesis disorders and singleenzyme defi ciencies that result in severe metabolic diseases that are often lethal in early childhood. X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by the accumulation of VLCFA in tissues, progressive demyelination, and adrenocortical dysfunction ( 4 ). X-ALD is caused by mutations in ABCD1 (D1), an ATP binding cassette (ABC) half transporter that presumably mediates the transport of very-long-chain acylCoAs into peroxisomes ( 5 ). D1 is the founding member of a quartet of ABC half-transporters that contain peroxisomal targeting sequences and form heterodimers in vitro ( 6 ). However, homodimers appear to be preferred in vivo, and each subfamily member has a unique tissue distribution ( 7,8 ).The closest paralog to D1 is D2, which shares 66% amino acid identity and is expressed in the adrenal, brain, and liver ( 9 ). Expression of a D2 transgene in D1-defi cient mice partially corrected the phenotype in this mouse Abstract The ATP binding cassette transporter, ABCD2 (D2), is a peroxisomal protein whose mRNA has been detect ed in the adrenal, brain, liver, and fat. Although the role of this transporter in neural tissues has been studied, its function in adipose tissue remains unexplored. The level of immunoreactive D2 in epididymal fat is >50-fold of that found in brain or adrenal. D2 is highly enriched in adipocytes and is upregulated during adipogenesis but is not essen tial for adipocyte differentiation or lipid accumulation in day 13.5 mouse embryonic fi broblasts isolated from D2-defi cient (D2 ؊ / ؊ ) mice. Although no differences were appreci ated in differentiation percentage, total lipid accumulation was greater in D2 ؊ / ؊ adipocytes compared with the wild type. These results were consistent with in vivo observa tions in which no signifi cant differences in adiposity or adipocyte diameter between wild-type and D2؊ / ؊ mice were observed. D2

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“…PPARs have been the object of great attention as pharmacological targets because they have been shown to be involved in key physiological functions (lipid and glucose homeostasis, inflammatory processes, and adipogenesis) (Fruchart et al, 1999;Rosen et al, 2000;Kostadinova et al, 2005;Anghel and Wahli, 2007), and their malfunctioning has been associated with major disorders (metabolic syndrome, cardiovascular disease, and diabetes) (Lehmann et al, 1995;Berger and Moller, 2002;Evans et al, 2004;Kota et al, 2005). Moreover, these receptors represent novel potential pharmacological targets for the treatment of rare genetic diseases, such as X-linked adrenoleukodystrophy (Albet et al, 1997;Rampler et al, 2003;Pujol et al, 2004). Thus PPARs may represent a new, most relevant target for drug development and have the potential to lead to treatments in areas where there is a major need for novel, efficacious drugs.…”

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confidence: 99%

In Vivo Imaging Reveals Selective Peroxisome Proliferator Activated Receptor Modulator Activity of the Synthetic Ligand 3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)

Biserni

Giannessi²,

Sciarroni³

et al. 2008

Mol Pharmacol

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We report here the finding of a new pharmacological activity of a well known antagonist of peroxisome proliferator-activated receptors (PPARs). PPARs belong to the family of nuclear receptors playing a relevant role in mammalian physiology and are currently believed to represent a major target for the development of innovative drugs for metabolic and inflammatory diseases. In the present study, the application of reporter animal technology was instrumental to obtain the global pharmacological profiling indispensable to unraveling 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)-selective PPAR modulator (SPPARM) activity not underlined by previous traditional, cell-based studies. The results of this study, demonstrating the usefulness of reporter mice, may open new avenues for the development of innovative drugs for cardiovascular, endocrine, neural, and skeletal systems characterized by limited side effects.

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Evaluation of the therapeutic potential of PPARα agonists for X-linked adrenoleukodystrophy

Cited by 23 publications

References 30 publications

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression

ABCD2 is abundant in adipose tissue and opposes the accumulation of dietary erucic acid (C22:1) in fat

In Vivo Imaging Reveals Selective Peroxisome Proliferator Activated Receptor Modulator Activity of the Synthetic Ligand 3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)

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