Evaluation of the therapeutic potential of PPARalpha agonists for X-linked adrenoleukodystrophy.

6533b863fe1ef96bd12c7818

RESEARCH PRODUCT

Evaluation of the therapeutic potential of PPARalpha agonists for X-linked adrenoleukodystrophy.

Peter Brown Angela Netik Maurice Bugaut Johannes Berger Isabelle Weinhofer Sonja Forss-petter Jeffrey Alan Oplinger Heidelinde Rampler

subject

Male medicine.medical_specialty Endocrinology Diabetes and Metabolism Molecular Sequence Data Drug Evaluation Preclinical Peroxisome Proliferation Receptors Cytoplasmic and Nuclear Biology Sulfides ATP Binding Cassette Transporter Subfamily D Response Elements Biochemistry chemistry.chemical_compound Mice Endocrinology Internal medicine Gene expression Genetics medicine Animals Adrenoleukodystrophy Molecular Biology Gene Phenylurea Compounds Tetradecylthioacetic acid Brain medicine.disease Molecular biology Introns Mice Mutant Strains Sterol regulatory element-binding protein DNA-Binding Proteins Mice Inbred C57BL Butyrates Sterols Endocrinology chemistry Gene Expression Regulation Liver CCAAT-Enhancer-Binding Proteins Sterol Regulatory Element Binding Protein 1 Adrenoleukodystrophy ATP-Binding Cassette Transporters Sterol regulatory element-binding protein 2 Sterol Regulatory Element Binding Protein 1 Sterol Regulatory Element Binding Protein 2 Transcription Factors

description

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.

year	journal	country	edition	language
2003-12-05	Molecular genetics and metabolism

10.1016/j.ymgme.2003.09.002 https://pubmed.ncbi.nlm.nih.gov/14654352