title: Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function.
abstract: The histidine triad nucleotide-binding (HINT2) protein is a mitochondrial adenosine phosphoramidase expressed in the liver and pancreas. Its physiological function is unknown. To elucidate the role of HINT2 in liver physiology, the mouse Hint2 gene was deleted. Hint2(-/-) and Hint2(+/+) mice were generated in a mixed C57Bl6/J × 129Sv background. At 20 weeks, the phenotypic changes in Hint2(-/-) relative to Hint2(+/+) mice were an accumulation of hepatic triglycerides, decreased tolerance to glucose, a defective counter-regulatory response to insulin-provoked hypoglycemia, and an increase in plasma interprandial insulin but a decrease in glucose-stimulated insulin secretion and defective thermoregulation upon fasting. Leptin messenger RNA (mRNA) in adipose tissue and plasma leptin were elevated. In mitochondria from Hint2(-/-) hepatocytes, state 3 respiration was decreased, a finding confirmed in HepG2 cells where HINT2 mRNA was silenced. The linked complex II-III electron transfer was decreased in Hint2(-/-) mitochondria, which was accompanied by a lower content of coenzyme Q. Hypoxia-inducible factor-2α expression and the generation of reactive oxygen species were increased. Electron microscopy of mitochondria in Hint2(-/-) mice aged 12 months revealed clustered, fused organelles. The hepatic activities of 3-hydroxyacyl-coenzyme A dehydrogenase short chain and glutamate dehydrogenase (GDH) were decreased by 68% and 60%, respectively, without a change in protein expression. GDH activity was similarly decreased in HINT2-silenced HepG2 cells. When measured in the presence of purified sirtuin 3, latent GDH activity was recovered (126% in Hint2(-/-) versus 83% in Hint2(+/+) ). This suggests a greater extent of acetylation in Hint2(-/-) than in Hint2(+/+) .
  
  
  CONCLUSIONS
  Hint2/HINT2 positively regulates mitochondrial lipid metabolism and respiration and glucose homeostasis. The absence of Hint2 provokes mitochondrial deformities and a change in the pattern of acetylation of selected proteins.
authors.affiliation: Division of Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Juliette
authors.initials: J
authors.lastname: Martin
authors.forename: Olivier
authors.initials: O
authors.lastname: Maurhofer
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.forename: Giovanni
authors.initials: G
authors.lastname: Benard
authors.forename: Franziska
authors.initials: F
authors.lastname: Graber
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hahn
authors.forename: Anne
authors.initials: A
authors.lastname: Galinier
authors.forename: Caroline
authors.initials: C
authors.lastname: Hora
authors.forename: Anirudh
authors.initials: A
authors.lastname: Gupta
authors.forename: Gisèle
authors.initials: G
authors.lastname: Ferrand
authors.forename: Hans
authors.initials: H
authors.lastname: Hoppeler
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Marie V
authors.initials: MV
authors.lastname: St-Pierre
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D023421:Models, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D005969:Glutamate Dehydrogenase; D006867:Hydrolases; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000099162:Endothelial PAS Domain-Containing Protein 1; C582071:HINT2 protein, mouse