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


CONCLUSIONS
Obstructive jaundice downregulates hepatic PPAR-γ expression, which in turn may contribute to hypersensitivity towards endotoxin.
Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Xin
X
Lv
Jian-Gang
JG
Song
Hong-Hai
HH
Li
Jun-Ping
JP
Ao
Ping
P
Zhang
Ye-Sheng
YS
Li
Shao-Li
SL
Song
Xiang-Rui
XR
Wang
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000503:physiopathology; D019446:Endotoxemia / Q000503:physiopathology; D004731:Endotoxins / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D041781:Jaundice, Obstructive / Q000188:drug therapy / Q000503:physiopathology*; D008026:Ligation; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D020675:Peroxisomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015996:Survival Rate; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D004731:Endotoxins; D007004:Hypoglycemic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000410:Alanine Transaminase