title: Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II.
abstract: BACKGROUND
  Inflammatory states such as hepatitis and sepsis are frequently associated with alterations of bile acid synthesis. These conditions are mediated by bacterial wall products like lipopolysaccharide (LPS). Cholesterol 7-alpha hydroxylase is the rate-limiting enzyme of bile acid synthesis. Hydrophobic bile acids repress cholesterol 7-alpha hydroxylase transcription via binding to the farnesoid X receptor and interaction with the bile acid response element II in the cholesterol 7-alpha hydroxylase promoter.
  
  
  METHODS
  We tested the effect of LPS on hepatic expression of cholesterol 7-alpha hydroxylase in C57BL/6 mice and Wistar rats. Further, we analyzed the binding activity of hepatic nuclear extracts to the bile acid response element II and the binding site for farnesoid X receptor heterodimers (ecdysone response element).
  
  
  RESULTS
  Lipopolysaccharide caused a 100-fold reduction of cholesterol 7-alpha hydroxylase mRNA levels in mice and a 10-fold reduction in rats. Protein levels of cholesterol 7-alpha hydroxylase also decreased in both species. These changes inversely correlated with the increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element.
  
  
  CONCLUSIONS
  Lipopolysaccharide-induced repression of cholesterol 7-alpha hydroxylase occurs at the transcriptional level. The underlying mechanism involves an increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. In conclusion, the farnesoid and retinoid X receptors participate in LPS-induced cholesterol 7-alpha hydroxylase repression.
authors.affiliation: Abt. Innere Medizin I, Universität Ulm, Ulm, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Dikopoulos
authors.forename: H
authors.initials: H
authors.lastname: Weidenbach
authors.forename: G
authors.initials: G
authors.lastname: Adler
authors.forename: R M
authors.initials: RM
authors.lastname: Schmid
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics*; D015153:Blotting, Western; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004440:Ecdysone / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D020218:Response Elements; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D004440:Ecdysone; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated