Role of retinoid-X receptor-alpha in the suppression of rat bile acid coenzyme A-amino acid N-acyltransferase in liver during sepsis.
Sepsis causes intrahepatic cholestasis and leads to hepatic failure. However, the pathophysiology of hepatic events is unclear. Expression of rat hepatic bile acid coenzyme A-amino acid N-acyltransferase (rBAT), a major enzyme for the conjugation of bile acids, is significantly decreased during sepsis. rBAT transcriptional regulation is mainly by a heterodimer of farnesoid-X receptor (FXR) and retinoid-X receptor-alpha (RXR-alpha) via the inverted repeat 1 sequence. During sepsis, nuclear receptors and translocation of RXR-alpha from cytosol to nucleus decrease. The purpose of this study was to further clarify the mechanisms of RXR-alpha-mediated rBAT regulation during polymicrobial sepsis and with dexamethasone treatment. Polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP). Liver tissues obtained 3, 6, 9, and 18 h after CLP were studied, and hepatocytes were isolated from rats with sepsis. Post-CLP decreases were observed in mRNA levels of rBAT (6 h), protein levels of rBAT (6 h), RXR-alpha (6 h), and FXR (9 h). DNA binding activity of FXR/RXR significantly decreased at 6 h after CLP. Dexamethasone reversed sepsis-inhibited RXR-alpha expression and the binding activity of FXR/RXR to rBAT DNA as well as rBAT protein expression. The results suggest that suppression of rBAT occurs at the transcriptional level, and the decrease in RXR-alpha by septic insult may play a critical role in rBAT suppression at the early stage of polymicrobial sepsis.
Chen
Yen-Hsu
YH
Department of Internal Medicine, Division of Infectious Diseases, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hong
I-Chu
IC
Kuo
Kung-Kai
KK
Hsu
Hseng-Kuang
HK
Hsu
Chin
C
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D017093:Liver Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D003907:Dexamethasone; D000217:Acyltransferases; C026953:bile acid-CoA amino acid N-acyltransferase