| The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption. | |
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MedLine Citation:
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PMID: 11923102 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The molecular mechanisms of cholesterol absorption in the intestine are poorly understood. With the goal of defining candidate genes involved in these processes a fluorescence-activated cell sorter-based, retroviral-mediated expression cloning strategy has been devised. SCH354909, a fluorescent derivative of ezetimibe, a compound which blocks intestinal cholesterol absorption but whose mechanism of action is unknown, was synthesized and shown to block intestinal cholesterol absorption in rats. Pools of cDNAs prepared from rat intestinal cells enriched in enterocytes were introduced into BW5147 cells and screened for SCH354909 binding. Several independent clones were isolated and all found to encode the scavenger receptor class B, type I (SR-BI), a protein suggested by others to play a role in cholesterol absorption. SCH354909 bound to Chinese hamster ovary (CHO) cells expressing SR-BI in specific and saturable fashion and with high affinity (K(d) approximately 18 nM). Overexpression of SR-BI in CHO cells resulted in increased cholesterol uptake that was blocked by micromolar concentrations of ezetimibe. Analysis of rat intestinal sections by in situ hybridization demonstrated that SR-BI expression was restricted to enterocytes. Cholesterol absorption was determined in SR-B1 knockout mice using both an acute, 2-h, assay and a more chronic fecal dual isotope ratio method. The level of intestinal cholesterol uptake and absorption was similar to that seen in wild-type mice. When assayed in the SR-B1 knockout mice, the dose of ezetimibe required to inhibit hepatic cholesterol accumulation induced by a cholesterol-containing 'western' diet was similar to wild-type mice. Thus, the binding of ezetimibe to cells expressing SR-B1 and the functional blockade of SR-B1-mediated cholesterol absorption in vitro suggest that SR-B1 plays a role in intestinal cholesterol metabolism and the inhibitory activity of ezetimibe. In contrast studies with SR-B1 knockout mice suggest that SR-B1 is not essential for intestinal cholesterol absorption or the activity of ezetimibe. |
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Authors:
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Scott W Altmann; Harry R Davis; Xiaorui Yao; Maureen Laverty; Douglas S Compton; Li-ji Zhu; James H Crona; Mary Ann Caplen; Lizbeth M Hoos; Glen Tetzloff; Tony Priestley; Duane A Burnett; Catherine D Strader; Michael P Graziano |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: 1580 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2002 Jan |
Date Detail:
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Created Date: 2002-03-29 Completed Date: 2002-05-24 Revised Date: 2005-11-17 |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
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Languages: eng Pagination: 77-93 Citation Subset: IM |
Affiliation:
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Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. scott.altmann@spcorp.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticholesteremic Agents / pharmacology Antigens, CD36 / biosynthesis, genetics, metabolism* Azetidines / pharmacology CHO Cells Cholesterol / blood, metabolism* Cloning, Molecular Cricetinae Dose-Response Relationship, Drug Flow Cytometry Gene Library In Situ Hybridization Intestinal Absorption / drug effects Intestines / metabolism* Liver / drug effects, metabolism Male Membrane Proteins* Mice Mice, Knockout Microscopy, Fluorescence RNA, Messenger / metabolism Rats Rats, Sprague-Dawley Receptors, Immunologic* Receptors, Lipoprotein* Receptors, Scavenger Scavenger Receptors, Class B |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Antigens, CD36; 0/Azetidines; 0/Membrane Proteins; 0/RNA, Messenger; 0/Receptors, Immunologic; 0/Receptors, Lipoprotein; 0/Receptors, Scavenger; 0/Scarb1 protein, mouse; 0/Scarb1 protein, rat; 0/Scavenger Receptors, Class B; 163222-33-1/ezetimibe; 57-88-5/Cholesterol |
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