title: Thioesterase superfamily member 2/acyl-CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolism.
abstract: Members of the acyl-CoA thioesterase (Acot) gene family catalyze the hydrolysis of fatty acyl-CoAs, but their biological functions remain unknown. Thioesterase superfamily member 2 (Them2; synonym Acot13) is a broadly expressed mitochondria-associated Acot. Them2 was previously identified as an interacting protein of phosphatidylcholine transfer protein (PC-TP). Pctp(-/-) mice exhibit altered fatty acid metabolism that is accompanied by reduced hepatic glucose production. To examine the role of Them2 in regulating hepatic lipid and glucose homeostasis, we generated Them2(-/-) mice. In livers of Them2(-/-) mice compared with Them2(+/+) controls, a 1.9-fold increase in the K(m) of mitochondrial thioesterase activity was accompanied by a 28% increase in fatty acyl-CoA concentration. A reciprocal 23% decrease in free fatty acid concentration was associated with reduced activation of peroxisome proliferator-activated receptor α. However, fatty acid oxidation rates were preserved in livers of Them2(-/-) mice, suggesting that Them2 functions to limit β-oxidation. Hepatic glucose production was also decreased by 45% in the setting of reduced hepatocyte nuclear factor 4α (HNF4α) expression. When fed a high-fat diet, Them2(-/-) mice were resistant to increases in hepatic glucose production and steatosis. These findings reveal key roles for Them2 in the regulation of hepatic metabolism, which are potentially mediated by PC-TP-Them2 interactions.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Kang
authors.forename: Michele W
authors.initials: MW
authors.lastname: Niepel
authors.forename: Shuxin
authors.initials: S
authors.lastname: Han
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawano
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D017931:DNA Primers; D004734:Energy Metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C544602:Acot13 protein, mouse; D013869:Thiolester Hydrolases; D005947:Glucose