Document Detail

Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy.
MedLine Citation:
PMID:  22560224     Owner:  NLM     Status:  MEDLINE    
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.
Brian York; Erin L Reineke; Jørn 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 Newgard; Bert W O'Malley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell metabolism     Volume:  15     ISSN:  1932-7420     ISO Abbreviation:  Cell Metab.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-07     Completed Date:  2012-10-03     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  101233170     Medline TA:  Cell Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  752-63     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Carnitine Acyltransferases / deficiency,  genetics*,  metabolism*
Fatty Acids / genetics,  metabolism
Gene Expression Regulation
Hyperammonemia / genetics,  metabolism
Hypoglycemia / genetics,  metabolism
Ketosis / genetics,  metabolism
Lipid Metabolism
Mice, Transgenic
Muscle, Skeletal / metabolism
Muscular Diseases / enzymology,  genetics*,  metabolism*
Nuclear Receptor Coactivator 3 / deficiency,  genetics*,  metabolism*
Grant Support
P01 HD08818-37/HD/NICHD NIH HHS; P30 DK079638/DK/NIDDK NIH HHS; P30 DK079638/DK/NIDDK NIH HHS; P30 DK079638-05/DK/NIDDK NIH HHS; P30 HD024064/HD/NICHD NIH HHS; R01 CA112403/CA/NCI NIH HHS; R01 CA112403/CA/NCI NIH HHS; R01 CA112403-07/CA/NCI NIH HHS; R01 DK058242/DK/NIDDK NIH HHS; R01 DK058242/DK/NIDDK NIH HHS; R01 DK058242-09/DK/NIDDK NIH HHS; R01 HD007857/HD/NICHD NIH HHS; R01 HD008188/HD/NICHD NIH HHS; R01 HD008188-37/HD/NICHD NIH HHS; R01 HD008188-38S1/HD/NICHD NIH HHS; R01 NS029709/NS/NINDS NIH HHS; R01HD8188-38S1/HD/NICHD NIH HHS; U19 DK062434/DK/NIDDK NIH HHS; U19 DK062434-08/DK/NIDDK NIH HHS; U19 DK62434-08/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Fatty Acids; EC 2.3.1.-/Carnitine Acyltransferases; EC Receptor Coactivator 3

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