Document Detail


Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters.
MedLine Citation:
PMID:  18718997     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Niemann-Pick C1-like 1 (NPC1L1) facilitates the uptake of sterols into the enterocyte and is the target of the novel cholesterol absorption inhibitor, ezetimibe. These studies used the Golden Syrian hamster as a model to delineate the changes in the relative mRNA expression of NPC1L1 and other proteins that regulate sterol homeostasis in the enterocyte during and following cessation of ezetimibe treatment and also to address the clinically important question of whether the marked inhibition of cholesterol absorption alters biliary lipid composition. In hamsters fed a low-cholesterol, low-fat basal diet, the abundance of mRNA for NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder. In the first study, female hamsters were fed the basal diet containing ezetimibe at doses up to 2.0 mg.day(-1).kg body wt(-1). At this dose, cholesterol absorption fell by 82%, fecal neutral sterol excretion increased by 5.3-fold, and hepatic and intestinal cholesterol synthesis increased more than twofold, but there were no significant changes in either fecal bile acid excretion or biliary lipid composition. The ezetimibe-induced changes in intestinal cholesterol handling were reversed when treatment was withdrawn. In a second study, male hamsters were given a diet enriched in cholesterol and safflower oil without or with ezetimibe. The lipid-rich diet raised the absolute and relative cholesterol levels in bile more than fourfold. This increase was largely prevented by ezetimibe. These data are consistent with the recent finding that ezetimibe treatment significantly reduced biliary cholesterol saturation in patients with gallstones.
Authors:
Mark A Valasek; Joyce J Repa; Gang Quan; John M Dietschy; Stephen D Turley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-08-21
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  295     ISSN:  0193-1857     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-16     Completed Date:  2008-11-26     Revised Date:  2010-09-22    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G813-22     Citation Subset:  IM    
Affiliation:
Dept. of Internal Medicine, Univ. of Texas Southwestern Medical School, Dallas, TX 75390-9151, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Azetidines / adverse effects,  pharmacology*
Bile / metabolism*
Cholesterol / metabolism*
Cholesterol, Dietary / pharmacology
Cricetinae
Dietary Fats / administration & dosage*
Feces / chemistry
Female
Intestinal Absorption / drug effects
Intestine, Small / drug effects
Liver / drug effects,  metabolism
Male
Membrane Transport Proteins / drug effects*,  physiology
Mesocricetus
Substance Withdrawal Syndrome / physiopathology
Grant Support
ID/Acronym/Agency:
GM07062/GM/NIGMS NIH HHS; R37 HL09610/HL/NHLBI NIH HHS; T32 DK07745/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Azetidines; 0/Cholesterol, Dietary; 0/Dietary Fats; 0/Membrane Transport Proteins; 163222-33-1/ezetimibe; 57-88-5/Cholesterol
Comments/Corrections

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


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