title: Thioesterase superfamily member 2 (Them2) and phosphatidylcholine transfer protein (PC-TP) interact to promote fatty acid oxidation and control glucose utilization.
abstract: Thioesterase superfamily member 2 (Them2) is a mitochondrion-associated long-chain fatty acyl coenzyme A (CoA) thioesterase that is highly expressed in the liver and oxidative tissues. Them2 activity in vitro is increased when it interacts with phosphatidylcholine transfer protein (PC-TP), a cytosolic lipid binding protein. Them2-/- and Pctp-/- mice exhibit enhanced hepatic insulin sensitivity and increased adaptive thermogenesis, and Them2-/- mice are also resistant to diet-induced hepatic steatosis. Although we showed previously that a Them2-PC-TP complex suppresses insulin signaling, the enzymatic activity of Them2 suggests additional direct involvement in regulating hepatic nutrient homeostasis. Here we used cultured primary hepatocytes to elucidate biochemical and cellular mechanisms by which Them2 and PC-TP regulate lipid and glucose metabolism. Under conditions simulating fasting, Them2-/- and Pctp-/- hepatocytes each exhibited decreased rates of fatty acid oxidation and gluconeogenesis. In results indicative of Them2-dependent regulation by PC-TP, chemical inhibition of PC-TP failed to reproduce these changes in Them2-/- hepatocytes. In contrast, rates of glucose oxidation and lipogenesis in the presence of high glucose concentrations were decreased only in Them2-/- hepatocytes. These findings reveal a primary role for Them2 in promoting mitochondrial oxidation of fatty acids and glucose in the liver.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Baran A
authors.initials: BA
authors.lastname: Ersoy
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Nishiumi
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Japan Department of Internal Medicine related, Division of Metabolomics Research, Kobe University Graduate School of Medicine, Kobe, Japan Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA dcohen@partners.org.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D049294:Phospholipid Transfer Proteins / Q000235:genetics*; D011485:Protein Binding; D022722:Thermogenesis / Q000235:genetics; D013869:Thiolester Hydrolases / Q000235:genetics*
chemical_list: D005227:Fatty Acids; D049294:Phospholipid Transfer Proteins; C544602:Acot13 protein, mouse; D013869:Thiolester Hydrolases; D005947:Glucose
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