Ablation of Steroid Receptor Coactivator-3 Resembles the Human CACT Metabolic Myopathy

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• 作者：Brian York¹ ; ⁹ ; Erin  ; L. Reineke¹ ; ⁹ ; Jø ; rn  ; V. Sagen² ; ³ ; Bryan  ; C. Nikolai¹ ; Suoling Zhou¹ ; Jean-Francois Louet¹ ; Atul  ; R. Chopra¹ ; Xian Chen¹ ; Graham Reed⁴ ; Jeffrey Noebels⁴ ; Adekunle  ; M. Adesina⁵ ; Hui Yu⁶ ; Lee-Jun  ; C. Wong⁶ ; Anna Tsimelzon⁷ ; Susan Hilsenbeck⁷ ; Robert  ; D. Stevens⁸ ; Brett  ; R. Wenner⁸ ; Olga Ilkayeva⁸ ; Jianming Xu¹ ; Christopher  ; B. Newgard⁸ ; ⁹ ; Bert  ; W. O'Malley¹ ; ⁹ ; ^{berto@bcm.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：752-763
• 文件大小：1255 K

摘要

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Summary

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 尾-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.