| Multiple mechanisms limit the accumulation of unesterified cholesterol in the small intestine of mice deficient in both ACAT2 and ABCA1. | |
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MedLine Citation:
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PMID: 20724527 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cholesterol homeostasis in the enterocyte is regulated by the interplay of multiple genes that ultimately determines the net amount of cholesterol reaching the circulation from the small intestine. The effect of deleting these genes, particularly acyl CoA:cholesterol acyl transferase 2 (ACAT2), on cholesterol absorption and fecal sterol excretion is well documented. We also know that the intestinal mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1) increases in Acat2(-/-) mice. However, none of these studies has specifically addressed how ACAT2 deficiency impacts the relative proportions of esterified and unesterified cholesterol (UC) in the enterocyte and whether the concurrent loss of ABCA1 might result in a marked buildup of UC. Therefore, the present studies measured the expression of numerous genes and related metabolic parameters in the intestine and liver of ACAT2-deficient mice fed diets containing either added cholesterol or ezetimibe, a selective sterol absorption inhibitor. Cholesterol feeding raised the concentration of UC in the small intestine, and this was accompanied by a significant reduction in the relative mRNA level for Niemann-Pick C1-like 1 (NPC1L1) and an increase in the mRNA level for both ABCA1 and ABCG5/8. All these changes were reversed by ezetimibe. When mice deficient in both ACAT2 and ABCA1 were fed a high-cholesterol diet, the increase in intestinal UC levels was no greater than it was in mice lacking only ACAT2. This resulted from a combination of compensatory mechanisms including diminished NPC1L1-mediated cholesterol uptake, increased cholesterol efflux via ABCG5/8, and possibly rapid cell turnover. |
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Authors:
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Stephen D Turley; Mark A Valasek; Joyce J Repa; John M Dietschy |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-19 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 299 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-29 Completed Date: 2010-11-12 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
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Languages: eng Pagination: G1012-22 Citation Subset: IM |
Affiliation:
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Dept. of Internal Medicine, Univ. of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75390-9151, USA. stephen.turley@utsouthwestern.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics,
metabolism* Analysis of Variance Animals Azetidines / pharmacology Cholesterol / metabolism* Diet Esterification / drug effects Homeostasis / drug effects Intestinal Mucosa / drug effects, metabolism* Intestine, Small / drug effects, metabolism* Mice Mice, Knockout RNA, Messenger / genetics, metabolism Sterol O-Acyltransferase / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK078592/DK/NIDDK NIH HHS; GM07062/GM/NIGMS NIH HHS; HL09610/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Azetidines; 0/RNA, Messenger; 163222-33-1/ezetimibe; 57-88-5/Cholesterol; EC 2.3.1.26/Sterol O-Acyltransferase; EC 2.3.1.26/sterol O-acyltransferase 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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