title: Hepatic SRC-1 activity orchestrates transcriptional circuitries of amino acid pathways with potential relevance for human metabolic pathogenesis.
abstract: Disturbances in amino acid metabolism are increasingly recognized as being associated with, and serving as prognostic markers for chronic human diseases, such as cancer or type 2 diabetes. In the current study, a quantitative metabolomics profiling strategy revealed global impairment in amino acid metabolism in mice deleted for the transcriptional coactivator steroid receptor coactivator (SRC)-1. Aberrations were hepatic in origin, because selective reexpression of SRC-1 in the liver of SRC-1 null mice largely restored amino acids concentrations to normal levels. Cistromic analysis of SRC-1 binding sites in hepatic tissues confirmed a prominent influence of this coregulator on transcriptional programs regulating amino acid metabolism. More specifically, SRC-1 markedly impacted tyrosine levels and was found to regulate the transcriptional activity of the tyrosine aminotransferase (TAT) gene, which encodes the rate-limiting enzyme of tyrosine catabolism. Consequently, SRC-1 null mice displayed low TAT expression and presented with hypertyrosinemia and corneal alterations, 2 clinical features observed in the human syndrome of TAT deficiency. A heterozygous missense variant of SRC-1 (p.P1272S) that is known to alter its coactivation potential, was found in patients harboring idiopathic tyrosinemia-like disorders and may therefore represent one risk factor for their clinical symptoms. Hence, we reinforce the concept that SRC-1 is a central factor in the fine orchestration of multiple pathways of intermediary metabolism, suggesting it as a potential therapeutic target that may be exploitable in human metabolic diseases and cancer.
authors.affiliation: Departments of Molecular and Cellular Biology (M.T.-L., B.Y., K.T., E.S., S.Z., J.X., B.W.O., J.-F.L.), Urology (M.T.-L.), and Molecular and Human Genetics (H.Y., L.-J.C.W.), Baylor College of Medicine, Houston, Texas 77030; Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology (R.D.S., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; Laboratory of Genetics, Immunology and Human Pathologies (H.B.), Faculty of Mathematical, Physical, and Natural Sciences of Tunis, Tunis EL Manar University, Tunis 2092, Tunisia; and Centre Méditerranéen de Médecine Moléculaire (H.B., J.-F.L.), Inserm 1065, Nice 06204, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Tannour-Louet
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.forename: Ke
authors.initials: K
authors.lastname: Tang
authors.forename: Erin
authors.initials: E
authors.lastname: Stashi
authors.forename: Hichem
authors.initials: H
authors.lastname: Bouguerra
authors.forename: Suoling
authors.initials: S
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Louet
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014444:Tyrosine Transaminase / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D056920:Nuclear Receptor Coactivator 1; D014444:Tyrosine Transaminase