Original Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 28, 2011; 17(48): 5267-5273
Published online Dec 28, 2011. doi: 10.3748/wjg.v17.i48.5267
Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive jaundice
Xin Lv, Jian-Gang Song, Hong-Hai Li, Jun-Ping Ao, Ping Zhang, Ye-Sheng Li, Shao-Li Song, Xiang-Rui Wang
Xin Lv, Jian-Gang Song, Xiang-Rui Wang, Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Xin Lv, Department of Anesthesiology, Shanghai Pneumology Hospital, Tongji University, School of Medicine, Shanghai 200433, China
Hong-Hai Li, Jun-Ping Ao, Ping Zhang, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Cancer Institute, Shanghai 200127, China
Ye-Sheng Li, Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China
Shao-Li Song, Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Author contributions: Lv X, Song JG contributed equally to this work, performed the majority of experiments and wrote the manuscript; Li HH, Ao JP, Zhang P, Li YS, Song SL performed part of experiment and statistical analysis; Wang XR designed the study.
Supported by China Postdoctoral Science Foundation, No. 20080440626; National Natural Science Foundation of China, No. 30700788 and No. 81001545; and Shanghai Leading Academic Discipline Project, No. S30203
Correspondence to: Xiang-Rui Wang, MD, Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.1630,Dongfang Road, Shanghai 200127, China. xiangruiwang@163.com
Telephone: +86-21-68383198 Fax: +86-21-68383198
Received: May 30, 2011
Revised: August 25, 2011
Accepted: September 2, 2011
Published online: December 28, 2011
Abstract

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-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 PPAR-γ gene expression was downregulated at both the mRNA and protein levels. In a parallel group, serum levels of pro-inflammatory cytokines were nearly undetectable 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-α, 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-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 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 towards endotoxin.

Keywords: Obstructive jaundice; Endotoxemia; Liver; Peroxisome proliferator-activated receptor-γ; Rosiglitazone