Sorbitol dehydrogenase inhibitor protects the liver from ischemia/reperfusion-induced injury via elevated glycolytic flux and enhanced sirtuin 1 activity.

Abstract

Sorbitol dehydrogenase (SDH), a key enzyme of the polyol pathway, has recently been demonstrated to have an important role in mediating tissue ischemia/reperfusion (I/R) injury. The present study investigated how this enzyme may affect the ischemic liver and the mechanism underlying its effect. Firstly, C57BL/6 mice were subjected to oral administration of CP-470,711 (5 mg/kg body weight/day for five days) and 70% hepatic I/R. Next the present study further investigated the changes in liver function, histology, inflammation, apoptosis and necrosis; the cytosolic adenosine triphosphate (ATP) and nictotinamide adenine dinucleotide [NAD(H)] contents and the protein level of caspase 3 and sirtuin 1 (SIRT1). The data demonstrated that sorbitol dehydrogenase inhibitor (SDI)-administration significantly alleviated I/R-induced liver injury, palliated histological changes and lowered the level of hepatocyte apoptosis and necrosis. In addition, SDI-pretreatment in ischemic liver markedly maintained the cytosolic ATP and NAD(H) proportion, enhanced SIRT1 and suppressed the activation of caspase 3 at the protein level. The findings in the present study revealed that the flux through SDH may render the liver more vulnerable to I/R-induced injury and interventions targeting this enzyme may provide a novel adjunctive approach to protect from severe tissue injury following liver ischemia.

• Authors: Changhe Zhang, Xiangcheng Li, Qinhong Liu
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 11 Issue 1 Pg. 283-8 (Jan 2015) ISSN: 1791-3004 [Electronic] Greece
• PMID: 25333577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Protective Agents
• NAD
• L-Iditol 2-Dehydrogenase
• Caspase 3
• Sirtuin 1

Topics

• Animals
• Caspase 3 (metabolism)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glycolysis (drug effects)
• Hepatocytes (drug effects, metabolism, pathology)
• L-Iditol 2-Dehydrogenase (antagonists & inhibitors)
• Liver (blood supply, drug effects, metabolism, pathology)
• Male
• Mice
• NAD (metabolism)
• Protective Agents (pharmacology)
• Reperfusion Injury (drug therapy, metabolism, pathology)
• Sirtuin 1 (metabolism)