title: Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.
abstract: 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.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Brian
authors: B
authors: York
authors: Jørn V
authors: JV
authors: Sagen
authors: Anna
authors: A
authors: Tsimelzon
authors: Jean-Francios
authors: JF
authors: Louet
authors: Atul R
authors: AR
authors: Chopra
authors: Erin L
authors: EL
authors: Reineke
authors: Suoling
authors: S
authors: Zhou
authors: Robert D
authors: RD
authors: Stevens
authors: Brett R
authors: BR
authors: Wenner
authors: Olga
authors: O
authors: Ilkayeva
authors: James R
authors: JR
authors: Bain
authors: Jianming
authors: J
authors: Xu
authors: Susan G
authors: SG
authors: Hilsenbeck
authors: Christopher B
authors: CB
authors: Newgard
authors: Bert W
authors: BW
authors: O'Malley
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000172:deficiency / Q000235:genetics; D051958:Nuclear Receptor Coactivator 2 / Q000172:deficiency / Q000235:genetics; D056921:Nuclear Receptor Coactivator 3 / Q000172:deficiency / Q000235:genetics; D056918:Nuclear Receptor Coactivators / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D005947:Glucose