title: 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.affiliation: Department of General Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China.
authors.forename: Changhe
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of General Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009243:NAD / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D020011:Protective Agents; D009243:NAD; D007064:L-Iditol 2-Dehydrogenase; D053148:Caspase 3; D056564:Sirtuin 1