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J. Biol. Chem., Vol. 278, Issue 34, 31610-31620, August 22, 2003
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Multiple, Independently Regulated Pathways of Cholesterol Transport across the Intestinal Epithelial Cells*
From the Departments of Anatomy and Cell Biology, and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203
The present study provides a new understanding about the mechanisms involved in cholesterol absorption by the intestinal cells. Contrary to general belief, our data show that newly absorbed cholesterol is neither immediately available for secretion with apoB lipoproteins nor exclusively secreted as part of chylomicrons. Based on our data, cholesterol transport by enterocytes can be broadly classified into two independently modulated, apoB-dependent and -independent, pathways. Cholesterol secretion by the apoB-dependent pathway is induced by oleic acid, is repressed by microsomal triglyceride transfer protein inhibitors, and occurs only with larger apoB-containing lipoproteins. ApoB-independent pathways do not require microsomal triglyceride transfer protein and involve efflux mediated by ABCA1, high density lipoprotein assembly, and possibly other unknown mechanisms. There are at least two different metabolic pools of cholesterol. The newly absorbed and pre-absorbed cholesterol are preferentially secreted via apoB-independent and apoB-dependent pathways, respectively. In contrast to compartmentalization for secretion, these two metabolic pools are equally accessible for cellular esterification. The esterified cholesterol is mainly secreted by the apoB-dependent pathway, whereas both the pathways are involved in the secretion of free cholesterol. Thus, enterocytes transport exogenous cholesterol by several independently regulated pathways raising the possibility that targeting of apoB-independent pathways may result in selective inhibition of cholesterol transport without affecting triglyceride transport.
Received for publication, February 3, 2003 , and in revised form, May 19, 2003.
* This work was supported by National Institutes of Health Grants DK46900 and HL64272 and an Established Investigator award by the American Heart Association (to M. M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Depts. of Anatomy and Cell
Biology, and Pediatrics, State University of New York Downstate Medical
Center, 450 Clarkson Ave., Box 5, Brooklyn, NY 11203. Fax: 718-270-2462;
E-mail:
mahmood.hussain{at}downstate.edu.
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