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Evaluation of the therapeutic potential of PPARalpha agonists for X-linked adrenoleukodystrophy
Heidelinde Rampler1, Isabelle Weinhofer, Angela Netik
1Brain Research Institute, University of Vienna, Vienna, Austria.
Abstract:
Adrenoleukodystrophy protein (ABCD1), a peroxisomal membrane protein, is mutated in patients affected by X-linked adrenoleukodystrophy (X-ALD). Adrenoleukodystrophy-related protein (ABCD2) is the closest relative of ABCD1. Pharmacological induction of ABCD2 gene expression has been proposed as a novel therapy strategy for X-ALD. Fibrates induce peroxisome proliferation and Abcd2 expression in rodent liver. Here we evaluate the possibility of using peroxisome proliferator-activated receptor alpha (PPARalpha) agonists for pharmacological induction of ABCD2 expression. In the liver of PPARalpha-deficient mice, both the constitutive and the fenofibrate-inducible Abcd2 gene expression was found to be PPARalpha-dependent. In the brain, PPARalpha-deficiency has no effect on Abcd2 expression. In mice orally treated with the novel, highly selective, and potent PPARalpha agonists GW 7647, GW 6867, and tetradecylthioacetic acid, Abcd2 expression was induced in liver and adrenal glands, but not in brain and testis. None of four putative PPREs identified in the 5(')-flanking DNA and in intron 1 of the Abcd2 gene conferred fibrate response in luciferase reporter assays. Thus, although fibrate-mediated Abcd2 induction is PPARalpha-dependent, it appears to be an indirect mechanism. Within the mouse Abcd2 promoter, a putative sterol regulatory element (SRE) similar in sequence and position to the characterized SRE sequence of the human ABCD2 promoter, was identified. A PPARalpha dependent induction of the sterol regulatory-binding protein 2 (SREBP2) and a down-regulation of SREBP1c mRNA levels could be demonstrated after fenofibrate treatment of mice. Our results suggest that the PPARalpha agonist-mediated induction of Abcd2 expression seems to be indirect and possibly mediated by SREBP2.
Insights
Pharmacological induction of ABCD2 gene expression, a potential therapy for X-linked adrenoleukodystrophy (X-ALD), is PPARalpha-dependent but appears indirect. This mechanism may involve sterol regulatory-binding protein 2 (SREBP2) in liver and adrenal glands.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the Adrenoleukodystrophy protein (ABCD1) gene.
- Adrenoleukodystrophy-related protein (ABCD2) is a close relative of ABCD1, and its gene expression is being investigated as a potential therapeutic strategy for X-ALD.
- Fibrates are known to induce peroxisome proliferation and Abcd2 expression in rodent liver, suggesting a role for peroxisome proliferator-activated receptor alpha (PPARalpha).
Purpose of the Study:
- To evaluate the efficacy of peroxisome proliferator-activated receptor alpha (PPARalpha) agonists in pharmacologically inducing ABCD2 gene expression.
- To investigate the role of PPARalpha in the regulation of Abcd2 gene expression in different tissues.
- To elucidate the mechanism underlying fibrate-mediated Abcd2 induction.
Main Methods:
- Utilized PPARalpha-deficient mice to assess the dependence of Abcd2 gene expression on PPARalpha.
- Administered novel PPARalpha agonists (GW 7647, GW 6867, tetradecylthioacetic acid) to mice and analyzed Abcd2 expression in various tissues (liver, brain, adrenal glands, testis).
- Performed luciferase reporter assays to test the response of putative PPREs in the Abcd2 gene to fibrate treatment.
- Investigated the role of sterol regulatory element (SRE) and sterol regulatory-binding protein 2 (SREBP2) in Abcd2 regulation.
Main Results:
- Abcd2 gene expression, both constitutive and inducible, was PPARalpha-dependent in the liver but not in the brain.
- PPARalpha agonists induced Abcd2 expression in the liver and adrenal glands, but not in the brain or testis.
- No direct response was observed from putative PPREs in the Abcd2 gene, indicating an indirect induction mechanism.
- A PPARalpha-dependent induction of SREBP2 and down-regulation of SREBP1c mRNA were observed after fenofibrate treatment.
Conclusions:
- Fibrate-mediated induction of Abcd2 gene expression is PPARalpha-dependent but appears to be an indirect process.
- The induction of Abcd2 expression by PPARalpha agonists may be mediated by SREBP2, particularly in the liver and adrenal glands.
- These findings provide insights into the complex regulation of Abcd2 and suggest potential avenues for X-ALD therapeutic strategies.
