Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive jaundice  

作　　者：Xin Lv Jian-Gang Song Hong-Hai Li Jun-Ping Ao Ping Zhang Ye-Sheng Li Shao-Li Song Xiang-Rui Wang 

机构地区：[1]Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China [2]Department of Anesthesiology, Shanghai Pneumology Hospital, Tongii University, School of Medicine, Shanghai200433, China [3]State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Cancer Institute, Shanghai 200127, China [4]Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China [5]Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China

出　　处：《World Journal of Gastroenterology》2011年第48期5267-5273,共7页世界胃肠病学杂志（英文版）

基　　金：Supported by China Postdoctoral Science Foundation, No.20080440626;National Natural Science Foundation of China,No. 30700788 and No. 81001545;Shanghai Leading Academic Discipline Project, No. S30203

摘　　要：AIM: To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia.METHODS: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis,and electrophoretic mobility shift assay, respectively.BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operatedrats treated at a lethal dose of LPS (6 mg/kg, i.p.).RESULTS: PPAR-γ activity in rats undergoing BDL wassignificantly lower than in the sham-controls. Hepatic PPAR-γ gene expression was downregulated at both them RNA and protein levels. In a parallel group, serumlevels of pro-inflammatory cytokines were nearly unde-tectable in the sham-operated rats. When challenged with a non-lethal dose of LPS (3 mg/kg), the BDL ratshad approximately a 2.4-fold increase in serum IL-6,a 2.7 fold increase in serum TNF-α, 2.2-fold increasein serum IL-1 and 4.2-fold increase in serum ALT. Thesurvival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-α, IL-1β, IL-6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS (3 mg/kg). Also, the survival was improved by rosiglita zone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS (3 mg/kg).CONCLUSION: Obstructive jaundice downregulates hepatic PPAR-γ expression, which in turn may contributeto hypersensitivity towards endotoxin.AIM： To investigate the role of hepatic peroxisome proliferator-activated receptor-γ, （PPAR-γ,） in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS： Male Sprague-Dawley rats were subjectedto bile duct ligation （BDL）. Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide （LPS） injection （3 mg/kg, i.p.）. Additionally, the potential beneficial effects of the PPAR-γ, agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS （6 mg/kg, i.p.）. RESULTS： PPAR-γ activity in rats undergoing BDL was significantly lower than in the sham-controls. Hepatic PPARγ gene expression was downregulated at both the mRNA and protein levels. In a parallel group, serum levels of pro-inflammatory cytokines were nearly unde- tectable in the sham-operated rats. When challenged with a non-lethal dose of LPS （3 mg/kg）, the BDL rats had approximately a 2.4-fold increase in serum IL-6, a 2.7 fold increase in serum TNF-γ, 2.2-fold increase in serum IL-1 and 4.2-fold increase in serum ALT. The survival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-γ, IL- 113, IL-6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS （3 mg/kg）. Also, the survival was improved by rosiglitazone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS （3 mg/kg）. CONCLUSION： Obstructive jaundice downregulates hepatic PPAR-γ, expression, which in turn may contribute to hypersensitivity to

关 键 词：Obstructive jaundice ENDOTOXEMIA Liver Peroxisome proliferator-activated receptor-γ ROSIGLITAZONE 

分 类 号：R[医药卫生]