ArticleHepatology (Baltimore, Md.)2013
Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function.
Article in Hepatology (Baltimore, Md.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NADExperimental & molecular medicine · 2025Article
- Article
- HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.Journal of cellular and molecular medicine · 2024Article
- Two-Dimensional Polyacrylamide Gel Electrophoresis Coupled with Nanoliquid Chromatography-Tandem Mass Spectrometry-Based Identification of Differentially Expressed Proteins and Tumorigenic Pathways in the MCF7 Breast Cancer Cell Line Transfected for Jumping Translocation Breakpoint Protein Overexpression.International journal of molecular sciences · 2023Article
- HINT2 deficiency deteriorates oxidative stress in a mouse model of myocardial infarction.ESC heart failure · 2023Article
- Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury.Basic research in cardiology · 2021Article
- mMolecular cancer · 2019Article
- Article
- Proteomic changes in oocytes after in vitro maturation in lipotoxic conditions are different from those in cumulus cells.Scientific reports · 2019Article
- Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease.Hepatology communications · 2018Review
- The role of the mitochondrial calcium uniporter (MCU) complex in cancer.Pflugers Archiv : European journal of physiology · 2018Review
- NNMT activation can contribute to the development of fatty liver disease by modulating the NADScientific reports · 2018Article
- Restricted feeding modulates the daily variations of liver glutamate dehydrogenase activity, expression, and histological location.Experimental biology and medicine (Maywood, N.J.) · 2017Article
- Article
- Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.Human molecular genetics · 2015Article
- iTRAQ-based quantitative proteomic analysis of longissimus muscle from growing pigs with dietary supplementation of non-starch polysaccharide enzymes.Journal of Zhejiang University. Science. B · 2015Article
- Mitochondrial aldehyde dehydrogenase activation by Alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein E-knockout mice.Journal of the American Heart Association · 2014Article
- Widespread and enzyme-independent Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of the mitochondrial matrix.The Journal of biological chemistry · 2013Article
- Characterization of the effect of the mitochondrial protein Hint2 on intracellular Ca(2+) dynamics.Biophysical journal · 2013Article
- Structural characterization of human histidine triad nucleotide-binding protein 2, a member of the histidine triad superfamily.The FEBS journal · 2013Article
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
unlabelledThe 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(+/+) .
conclusionHint2/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.
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