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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.forename: Erin L
authors.initials: EL
authors.lastname: Reineke
authors.forename: Jørn V
authors.initials: JV
authors.lastname: Sagen
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Nikolai
authors.forename: Suoling
authors.initials: S
authors.lastname: Zhou
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Louet
authors.forename: Atul R
authors.initials: AR
authors.lastname: Chopra
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Graham
authors.initials: G
authors.lastname: Reed
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Noebels
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Susan
authors.initials: S
authors.lastname: Hilsenbeck
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Brett R
authors.initials: BR
authors.lastname: Wenner
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
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
mesh_terms: D000818:Animals; D002333:Carnitine Acyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics / Q000378:metabolism; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D007662:Ketosis / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids; D002333:Carnitine Acyltransferases; D056921:Nuclear Receptor Coactivator 3