@article{89955a4e9c184b0c939a974a51bcf80f,
title = "Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy",
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.",
author = "Brian York and Reineke, {Erin L.} and Sagen, {Jorn V.} and Nikolai, {Bryan C.} and Suoling Zhou and Louet, {Jean Francois} and Chopra, {Atul R.} and Xian Chen and Graham Reed and Jeffrey Noebels and Adesina, {Adekunle M.} and Hui Yu and Wong, {Lee Jun C.} and Anna Tsimelzon and Susan Hilsenbeck and Stevens, {Robert D.} and Wenner, {Brett R.} and Olga Ilkayeva and Jianming Xu and Newgard, {Christopher B.} and O'Malley, {Bert W.}",
note = "Funding Information: We especially thank Adam Dean and Pauline Grennan for technical assistance. Special thanks to Rainer Lanz for bioinformatic analysis of the CACT promoter. J{\o}rn V. Sagen is funded by the Norwegian Cancer Society, University of Bergen, Det regionale samarbeidsorganet (Helse Vest RHF and University of Bergen), and the Norwegian Society of Endocrinology. Thanks to Lawrence Chan and Pradip Saha at the NIDDK sponsored MMC Core at BCM under DERC (P30 DK079638) for assistance with the clamp studies. Also, we kindly thank Robert Ringseis for CACT luciferase reporter constructs. This work was supported by R01 DK058242 and R01 CA112403 to J. Xu; NURSA/NIDDK U19 DK62434-08 to B.W. O'Malley and C.B. Newgard; NIDDK PO1 HD08818-37 to B.W. O'Malley; and R01HD8188-38S1 to B. York and B.W O'Malley. ",
year = "2012",
month = may,
day = "2",
doi = "10.1016/j.cmet.2012.03.020",
language = "English (US)",
volume = "15",
pages = "752--763",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}