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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • York, B; Reineke, EL; Sagen, JV; Nikolai, BC; Zhou, S; Louet, J-F; Chopra, AR; Chen, X; Reed, G; Noebels, J; Adesina, AM; Yu, H; Wong, L-JC; Tsimelzon, A; Hilsenbeck, S; Stevens, RD; Wenner, BR; Ilkayeva, O; Xu, J; Newgard, CB; O'Malley, BW

Published Date

  • May 2, 2012

Published In

Volume / Issue

  • 15 / 5

Start / End Page

  • 752 - 763

PubMed ID

  • 22560224

Pubmed Central ID

  • PMC3349072

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2012.03.020


  • eng

Conference Location

  • United States