title: mPGES-2 deletion remarkably enhances liver injury in streptozotocin-treated mice via induction of GLUT2.
abstract: OBJECTIVE
  Microsomal prostaglandin E synthase-2 (mPGES-2) deletion does not influence in vivo PGE2 production and the function of this enzyme remains elusive. The present study was undertaken to investigate the role of mPGES-2 in streptozotocin (STZ)-induced type-1 diabetes and organ injuries.
  
  
  METHODS
  mPGES-2 wild type (WT) and knockout (KO) mice were treated by a single intraperitoneal injection of STZ at the dose of 120 mg/kg to induce type-1 diabetes. Subsequently, glycemic status and organ injuries were evaluated.
  
  
  RESULTS
  Following 4 days of STZ administration, mPGES-2 KO mice exhibited severe lethality in contrast to the normal phenotype observed in WT control mice. In a separate experiment, the analysis was performed at day 3 of the STZ treatment in order to avoid lethality. Blood glucose levels were similar between STZ-treated KO and WT mice. However, the livers of KO mice were yellowish with severe global hepatic steatosis, in parallel with markedly elevated liver enzymes and remarkable stomach expansion. However, the morphology of the other organs was largely normal. The STZ-treated KO mice displayed extensive hepatocyte apoptosis compared with WT mice in parallel with markedly enhanced inflammation and oxidative stress. More interestingly, a liver-specific 50% upregulation of GLUT2 was found in the KO mice accompanied with a markedly enhanced STZ accumulation and this induction of GLUT2 was likely to be associated with the insulin/SREBP-1c pathway. Primary cultured hepatocytes of KO mice exhibited an increased sensitivity to STZ-induced injury and higher cellular STZ content, which was markedly blunted by the selective GLUT2 inhibitor phloretin.
  
  
  CONCLUSIONS
  mPGES-2 deletion enhanced STZ-induced liver toxicity possibly via GLUT2-mediated STZ uptake, independently of diabetes mellitus.
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.|Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors: Ying
authors: Y
authors: Sun
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.
authors: Zhanjun
authors: Z
authors: Jia
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.
authors: Guangrui
authors: G
authors: Yang
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.
authors: Yutaka
authors: Y
authors: Kakizoe
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.|Institute of Hypertension, Sun Yat-sen University School of Medicine, Guangzhou, China.
authors: Mi
authors: M
authors: Liu
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.|Institute of Hypertension, Sun Yat-sen University School of Medicine, Guangzhou, China.
authors: Kevin T
authors: KT
authors: Yang
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.
authors: Ying
authors: Y
authors: Liu
authors: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors: Baoxue
authors: B
authors: Yang
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, United States.|Institute of Hypertension, Sun Yat-sen University School of Medicine, Guangzhou, China.
authors: Tianxin
authors: T
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D051273:Glucose Transporter Type 2 / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D013311:Streptozocin / Q000009:adverse effects*
chemical_list: D051273:Glucose Transporter Type 2; D007328:Insulin; C495683:Slc2a2 protein, rat; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013311:Streptozocin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat
keywords: Diabetes; Glucose transporter 2; Prostaglandin E(2); Streptozotocin; mPGES-2