York Brian, Sagen Jørn V, Tsimelzon Anna, Louet Jean-Francios, Chopra Atul R, Reineke Erin L, Zhou Suoling, Stevens Robert D, Wenner Brett R, Ilkayeva Olga, Bain James R, Xu Jianming, Hilsenbeck Susan G, Newgard Christopher B, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Endocrinol. 2013 Feb;27(2):366-80. doi: 10.1210/me.2012-1324. Epub 2013 Jan 11.
The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.
转录共调节因子这一迅速壮大的家族包括促进转录的共激活因子和具有相反功能的共抑制因子。近年来，共调节因子已成为代谢稳态的重要调节因子，包括p160类固醇受体共激活因子（SRC）家族。SRC家族成员在肝脏糖异生、脂肪吸收与储存以及骨骼肌脂肪酸氧化的控制中发挥着重要作用。为了更深入、更细致地了解SRC家族成员对代谢的影响，我们对SRC-1、SRC-2或SRC-3基因完全敲除（KO）小鼠的葡萄糖、脂肪酸和氨基酸代谢的关键代谢副产物进行了靶向代谢组学分析。我们在进食和禁食条件下，测量了从SRC-1、-2或-3基因敲除小鼠及其野生型同窝小鼠分离出的具有关键代谢功能的五个组织（肝脏、心脏、骨骼肌、大脑、血浆）中的氨基酸、酰基肉碱和有机酸，从而揭示了每个SRC独特的代谢功能。具体而言，SRC-1基因敲除对肝脏代谢的影响最为显著，而SRC-2似乎影响心脏代谢。相反，SRC-3基因敲除主要影响大脑和骨骼肌代谢。令人惊讶的是，我们发现很少有代谢物在三种SRC基因敲除模型中普遍发生变化。这项研究资源的结果表明，即使在同源的SRC家族中，共激活因子功能的代谢冗余也非常有限。此外，这项工作还证明了代谢组学可作为一种手段，用于识别转录共调节因子的新型代谢调节功能。
