These authors contributed equally to this work.
Article first published online: 22 APR 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 5, pages 2037–2048, May 2013
How to Cite
Martin, J., Maurhofer, O., Bellance, N., Benard, G., Graber, F., Hahn, D., Galinier, A., Hora, C., Gupta, A., Ferrand, G., Hoppeler, H., Rossignol, R., Dufour, J.-F. and St-Pierre, M. V. (2013), Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function. Hepatology, 57: 2037–2048. doi: 10.1002/hep.26060
Potential conflict of interest: Nothing to report.
This work was supported by Swiss National Foundation Grant 31003A-140930 (to J.-F. D.). J.-F. D. received funding from the European Community's Seventh Framework Programme under grant agreement HEALTH-F2-2009-241762 for the project FLIP. N. B. received a grant from INSERM-Région Aquitaine. J. M. received a fellowship from the European Association for the Study of the Liver.
- Issue published online: 22 APR 2013
- Article first published online: 22 APR 2013
- Accepted manuscript online: 7 SEP 2012 09:03AM EST
- Manuscript Accepted: 30 JUL 2012
- Manuscript Received: 5 NOV 2011
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+/+. Conclusion: 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. (HEPATOLOGY 2013)