Document Detail

Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression.
MedLine Citation:
PMID:  11701475     Owner:  NLM     Status:  MEDLINE    
Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPARalpha agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7alpha-hydroxylase enzyme activity and mRNA. The functional involvement of PPARalpha in the suppression of both enzymes was proven with the use of PPARalpha-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARalpha-null mice. A decreased bile acid production by PPARalpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.
S M Post; H Duez; P P Gervois; B Staels; F Kuipers; H M Princen
Related Documents :
8827695 - Prevention of cholesterol cholelithiasis by dietary unsaturated fats in hormone-treated...
6886565 - [24,25-3h]cholesterol: presence of tritium at additional sites in the side chain.
173965 - Synthesis of cholesterol esters in the plasma and liver of sheep.
185335 - Neurochemical findings in adreno-leukodystrophy.
11540925 - A reverse krebs cycle in photosynthesis: consensus at last.
12601005 - Vectorial acylation in saccharomyces cerevisiae. fat1p and fatty acyl-coa synthetase ar...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  21     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-11-09     Completed Date:  2001-12-07     Revised Date:  2012-01-30    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1840-5     Citation Subset:  IM    
Gaubius Laboratory, TNO-PG, Leiden, the Netherlands.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Bile Acids and Salts / biosynthesis*
Cells, Cultured
Cholesterol / metabolism*
Cholesterol 7-alpha-Hydroxylase / genetics,  metabolism
Clofibric Acid / analogs & derivatives*,  pharmacology*
Cytochrome P-450 CYP27A1
Cytochrome P-450 Enzyme System / genetics,  metabolism
Fibric Acids
Hepatocytes / drug effects,  metabolism
Hypolipidemic Agents / pharmacology*
Mice, Knockout
Pyrimidines / pharmacology*
RNA, Messenger / biosynthesis
Receptors, Cytoplasmic and Nuclear / genetics,  physiology*
Steroid Hydroxylases / genetics,  metabolism
Transcription Factors / genetics,  physiology*
Transcription, Genetic
Reg. No./Substance:
0/Bile Acids and Salts; 0/Fibric Acids; 0/Hypolipidemic Agents; 0/Pyrimidines; 0/RNA, Messenger; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 50892-23-4/pirinixic acid; 52214-84-3/ciprofibrate; 57-88-5/Cholesterol; 882-09-7/Clofibric Acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/Cytochrome P-450 CYP27A1; EC 1.14.-/Steroid Hydroxylases; EC protein, mouse; EC 7-alpha-Hydroxylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with corona...
Next Document:  Biphasic effects of 15-deoxy-delta(12,14)-prostaglandin J(2) on glutathione induction and apoptosis ...