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J. Biol. Chem., Vol. 283, Issue 29, 19967-19980, July 18, 2008

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Microsomal Triglyceride Transfer Protein Enhances Cellular Cholesteryl Esterification by Relieving Product Inhibition^*

Jahangir Iqbal, Lawrence L. Rudel, and M. Mahmood Hussain¹

From the Departments of Anatomy and Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203 and the Departments of Pathology and Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Cholesteryl ester synthesis by the acyl-CoA:cholesterol acyltransferase enzymes ACAT1 and ACAT2 is, in part, a cellular homeostatic mechanism to avoid toxicity associated with high free cholesterol levels. In hepatocytes and enterocytes, cholesteryl esters are secreted as part of apoB lipoproteins, the assembly of which is critically dependent on microsomal triglyceride transfer protein (MTP). Conditional genetic ablation of MTP reduces cholesteryl esters and enhances free cholesterol in the liver and intestine without diminishing ACAT1 and ACAT2 mRNA levels. As expected, increases in hepatic free cholesterol are associated with decreases in 3-hydroxy-3-methylglutaryl-CoA reductase and increases in ATP-binding cassette transporter 1 mRNA levels. Chemical inhibition of MTP also decreases esterification of cholesterol in Caco-2 and HepG2 cells. Conversely, coexpression of MTP and apoB in AC29 cells stably transfected with ACAT1 and ACAT2 increases cholesteryl ester synthesis. Liver and enterocyte microsomes from MTP-deficient animals synthesize lesser amounts of cholesteryl esters in vitro, but addition of purified MTP and low density lipoprotein corrects this deficiency. Enrichment of microsomes with cholesteryl esters also inhibits cholesterol ester synthesis. Thus, MTP enhances cellular cholesterol esterification by removing cholesteryl esters from their site of synthesis and depositing them into nascent apoB lipoproteins. Therefore, MTP plays a novel role in regulating cholesteryl ester biosynthesis in cells that produce lipoproteins. We speculate that non-lipoprotein-producing cells may use different mechanisms to alleviate product inhibition and modulate cholesteryl ester biosynthesis.

Received for publication, January 16, 2008 , and in revised form, May 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK46700 (to M. M. H.) and HL49373 (to L. L. R.). 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.

¹ To whom correspondence should be addressed. Tel.: 718-270-4790; Fax: 718-270-2462; E-mail: Mahmood.Hussain{at}downstate.edu.

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				T.-Y. Chang, B.-L. Li, C. C. Y. Chang, and Y. Urano Acyl-coenzyme A:cholesterol acyltransferases Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E1 - E9. [Abstract] [Full Text] [PDF]

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