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

Cell Metabolism
Brian YorkBert W O'malley

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.

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Citations

Aug 7, 2013·Seminars in Cell & Developmental Biology·Marco-Antonio Mendoza-Parra, Hinrich Gronemeyer
Jun 27, 2012·Nature Reviews. Endocrinology·David M Lonard, Bert W O'Malley
Oct 12, 2013·Annual Review of Medicine·Subhamoy DasguptaBert W O'Malley
Jun 24, 2014·Trends in Endocrinology and Metabolism : TEM·Erin StashiBert W O'Malley
May 6, 2014·Cell Metabolism·Laurent MouchiroudJohan Auwerx
Dec 18, 2015·Journal of Molecular Endocrinology·Inna Astapova
Jan 18, 2017·Cell Metabolism·Christopher B Newgard
Apr 11, 2018·Biology of Reproduction·Xuan ShaoYan-Ling Wang
Jul 16, 2014·Journal of Molecular Endocrinology·Subhamoy Dasgupta, Bert W O'Malley
Jan 21, 2014·Molecular Endocrinology·Massoud MotamedBert W O'Malley
Jul 20, 2019·Endocrine, Metabolic & Immune Disorders Drug Targets·Athina ChasapiGeorgia Sotiropoulou-Bonikou
Jun 19, 2019·Asian-Australasian Journal of Animal Sciences·Hyungkuen KimSung-Jo Kim
Dec 17, 2020·Human Molecular Genetics·Rodrigo Salazar-SilvaRegina Célia Mingroni-Netto
Feb 16, 2021·The Journal of Clinical Investigation·Liyan FanMukesh K Jain

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