Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy

Brian York, Erin L. Reineke, Jorn V. Sagen, Bryan C. Nikolai, Suoling Zhou, Jean Francois Louet, Atul R. Chopra, Xian Chen, Graham Reed, Jeffrey Noebels, Adekunle M. Adesina, Hui Yu, Lee Jun C. Wong, Anna Tsimelzon, Susan Hilsenbeck, Robert D. Stevens, Brett R. Wenner, Olga Ilkayeva, Jianming Xu, Christopher B. NewgardBert W. O'Malley

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression. Consistent with human cases of CACT deficiency, dietary rescue with short chain fatty acids drastically attenuates the clinical hallmarks of the disease in mice devoid of SRC-3. Collectively, our results position SRC-3 as a key regulator of β-oxidation. Moreover, these findings allow us to consider platform coactivators such as the SRCs as potential contributors to syndromes such as CACT deficiency, previously considered as monogenic.

Original languageEnglish (US)
Pages (from-to)752-763
Number of pages12
JournalCell Metabolism
Volume15
Issue number5
DOIs
StatePublished - May 2 2012

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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