Role of retinoid-X receptor-alpha in the suppression of rat bile acid coenzyme A-amino acid N-acyltransferase in liver during sepsis.

Abstract

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.

• Authors: Yen-Hsu Chen, I-Chu Hong, Kung-Kai Kuo, Hseng-Kuang Hsu, Chin Hsu
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 28 Issue 1 Pg. 65-70 (Jul 2007) ISSN: 1073-2322 [Print] United States
• PMID: 17483744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• RNA, Messenger
• Retinoid X Receptor alpha
• Dexamethasone
• Acyltransferases
• bile acid-CoA amino acid N-acyltransferase

Topics

• Acyltransferases (genetics, metabolism)
• Animals
• Base Sequence
• DNA Primers (genetics)
• Dexamethasone (pharmacology)
• Down-Regulation (drug effects)
• Liver (drug effects, metabolism)
• Liver Failure (etiology, genetics, metabolism, prevention & control)
• Male
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Retinoid X Receptor alpha (genetics, metabolism)
• Sepsis (complications, genetics, metabolism)