Role of retinoid x receptor in upregulation of hepaticrBAT by dexamethasone during sepsis

• Main Authors: I-Chu Hong, 洪羿筑
• Other Authors: Hseng-kuang Hsu
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/71970018045089210179

碩士 === 高雄醫學大學 === 醫學研究所碩士班 === 93 === Severe infection and sepsis may cause intrahepatic cholestasis and lead to hepatic dysfunction． Our previous results showed that the expression of bile acid CoA:amino acid N-acyltransferase (rBAT)， the enzyme required for bile salt formation，was significantly decreased in the liver at the early stage of sepsis. Additionally，bile salt export pump(BSEP)，a bile salt export pump， was also suppressed under septic insult．Both the transcriptions of rBAT and BSEP are regulated by the heterodimer of farnesoid X receptor(FXR) and retinoid X receptor (RXR) via IR-1 sequence．Therefore，the present study aimed to investigate the possible role of FXR/RXR upon the expressions of rBAT and BSEP． Animal model of sepsis was induced by cecal ligation and puncture (CLP)．To demonstrate wheather rBAT and BSEP protein and mRNA are modulated by FXR/RXR in CLP model．Liver tissues were sampled at 3、6、9 and 18 hours after CLP operation．Western blotting，RT-PCR and EMSA were performed to estimate protein content (FXR,RXR,BSEP,rBAT)，mRNA expressions (BSEP,rBAT) and DNA binding activities (FXR/RXR binding to IR-1)，respectively．Otherwise，hepatocytes were isolated from the septic rats at 6 hours after CLP to study the in vitro effect of dexamethasone，which enhances RXR expression，on the protein expressions of rBAT and BSEP． The results of in vivo experiments showed that: (1) The DNA binding activity of FXR/RXR was decreased at 6 hrs after CLP．Both protein and mRNA expression of rBAT、BSEP were also decreased．(2) Protein expression of RXR was decreased at 6 hrs after CLP，while FXR protein content was decreased at 9 hrs after CLP．We also tested the effect of dexamethasone of hepatocytes from the septic rats at 6 hrs after CLP．The results showed that: (1) Protein expression of RXR was increased and the DNA binding activity of FXR/RXR was also increased．(2) The protein expression of rBAT was significantly enhanced by dexamethasone treatment while no effect of dexamethasone on BSEP protein expression was observed． We conclude that (1) The rBAT and BSEP were modulated by FXR/RXR in CLP model．(2) The early suppression of RXR by septic insult may play an important role in hepatic dysfunction via regulating rBAT but not BSEP expression．(3) Dexamethasone may improve liver function in sepsis， via RXR modulation on rBAT．