Document Detail


Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse.
MedLine Citation:
PMID:  14684588     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND AIMS: Newly synthesised cholesterol contributes poorly to biliary lipid secretion but may assume greater importance when the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is upregulated. As this occurs in the gall stone susceptible C57L/J inbred mouse, we employed two cholesterol biosynthesis inhibitors, Tu 2208 and Ro 48-8071, potent inhibitors of squalene epoxidase and oxidosqualene-lanosterol cyclase, respectively, to assess their potential in preventing cholesterol cholelithiasis in the C57L/J mouse strain. Mice were fed a lithogenic diet comprising a balanced nutrient intake with 15% dairy fat, 1% cholesterol, and 0.5% cholic acid added.
METHODS: We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30-60 mg/kg/day) or Ro 48-8071 (30-100 mg/kg/day), while ingesting chow or the lithogenic diet.
RESULTS: Both agents reduced the gall stone prevalence rate from 73% to 17% in C57L/J mice, inhibited HMGR activity, and decreased hepatic cholesterol concentrations without appreciably influencing biliary cholesterol secretion. In C57L as well as AKR mice, both agents increased biliary phospholipid (which is mostly phosphatidylcholine) secretion rates and at the highest doses effectively reduced the biliary cholesterol saturation index.
CONCLUSIONS: Cholesterol biosynthesis inhibitors acting distally to squalene do not reduce biliary cholesterol secretion rates despite reductions in cholesterol biosynthesis and hepatocellular levels. However, they effectively prevent gall stone formation through stimulation of pathways that lead to enhanced biliary phospholipid secretion.
Authors:
G A Clarke; G Bouchard; B Paigen; M C Carey
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gut     Volume:  53     ISSN:  0017-5749     ISO Abbreviation:  Gut     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-19     Completed Date:  2004-02-26     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  136-42     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticholesteremic Agents / therapeutic use*
Benzophenones / therapeutic use
Bile / metabolism*
Bile Canaliculi / metabolism
Cholelithiasis / genetics,  metabolism,  prevention & control*
Cholesterol / biosynthesis*,  blood
Enzyme Inhibitors / therapeutic use
Genetic Predisposition to Disease
Intramolecular Transferases / antagonists & inhibitors
Lipids / secretion
Liver / metabolism
Male
Mice
Mice, Inbred AKR
Mice, Inbred C57BL
Oxygenases / antagonists & inhibitors
Phospholipids / secretion*
Squalene Monooxygenase
Thiophenes / therapeutic use
Grant Support
ID/Acronym/Agency:
DK 36588/DK/NIDDK NIH HHS; DK 38454/DK/NIDDK NIH HHS; DK 52911/DK/NIDDK NIH HHS; DK 753315/DK/NIDDK NIH HHS; DK51568/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Benzophenones; 0/Enzyme Inhibitors; 0/Lipids; 0/Phospholipids; 0/Thiophenes; 0/Tu 2208; 161582-11-2/Ro 48-8071; 57-88-5/Cholesterol; EC 1.13.-/Oxygenases; EC 1.14.99.7/Squalene Monooxygenase; EC 5.4.-/Intramolecular Transferases; EC 5.4.99.7/lanosterol synthase
Comments/Corrections

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


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