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