A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy

Meredith D. Hartley, Lisa L. Kirkemo, Tapasree Banerji, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disorder characterized by adrenal insufficiency and central nervous system (CNS) demyelination. All patients with X-ALD have the biochemical abnormality of elevated blood and tissue levels of very long chain fatty acids (VLCFAs), saturated fatty acids with 24 to 26 carbons. X-ALD results from loss of function mutations in the gene encoding the peroxisomal transporter ABCD1, which is responsible for uptake of VLCFAs into peroxisomes for degradation by oxidation. One proposed therapeutic strategy for genetic complementation of ABCD1 is pharmacologic upregulation of ABCD2, a gene encoding a homologous peroxisomal transporter. Here, we show that thyroid hormone or sobetirome, a clinical-stage selective thyroid hormone receptor agonist, increases cerebral Abcd2 and lowers VLCFAs in blood, peripheral organs, and brains of mice with defective Abcd1. These results support an approach to treating X-ALD that involves a thyromimetic agent that reactivates VLCFA disposal both in the periphery and the CNS.

Original languageEnglish (US)
Pages (from-to)1328-1338
Number of pages11
JournalEndocrinology
Volume158
Issue number5
DOIs
StatePublished - May 1 2017

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Adrenoleukodystrophy
Thyroid Hormones
Fatty Acids
Central Nervous System
Thyroid Hormone Receptors
Adrenal Insufficiency
Inborn Genetic Diseases
Peroxisomes
Demyelinating Diseases
Genes
Up-Regulation
Carbon
Hormones
Mutation
Brain

ASJC Scopus subject areas

  • Endocrinology

Cite this

A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy. / Hartley, Meredith D.; Kirkemo, Lisa L.; Banerji, Tapasree; Scanlan, Thomas (Tom).

In: Endocrinology, Vol. 158, No. 5, 01.05.2017, p. 1328-1338.

Research output: Contribution to journalArticle

Hartley, Meredith D. ; Kirkemo, Lisa L. ; Banerji, Tapasree ; Scanlan, Thomas (Tom). / A thyroid hormone-based strategy for correcting the biochemical abnormality in X-linked adrenoleukodystrophy. In: Endocrinology. 2017 ; Vol. 158, No. 5. pp. 1328-1338.
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