Molecular Mechanisms of Chylomicron Assembly

$307,167R01FY2011DKNIH

Suny Downstate Medical Center, Brooklyn NY

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Abstract

DESCRIPTION (provided by applicant): We observed that free and esterified cholesterol are transported by enterocytes via two independently regulated pathways. Here, we propose to study the role of various candidate proteins in the secretion of cholesterol by intestinal cells. The Aim 1 is to examine the role of Acyl-coA:cholesterol acyltransferase (ACAT) 2 and microsomal triglyceride transfer protein (MTP) in cholesterol esterification and secretion. We hypothesize that MTP regulates cholesterol ester secretion with chylomicrons by modulating esterification and accretion of cholesterol esters from cytosol to endoplasmic reticulum. First, we will study the role of, MTP in cholesterol esterification using mice deficient in ACAT2 and MTP and by co-expressing MTP with ACAT1 and ACAT2 in cells that do not express these proteins. Second, we will identify mechanisms by which MTP influences cholesterol esterification. Third, we will determine whether MTP facilitates the transport of cholesterol esters from cytosol to the endoplasmic reticulum. The Aim 2 is to explore the role of candidate proteins in the secretion of free cholesterol by enterocytes towards their basolateral side. Our hypothesis is that chylomicron assembly, efflux, and HDL assembly contribute to free cholesterol transport. We will examine the role of different candidate proteins in free cholesterol transport using enterocytes, everted sacs and mice. Importance of apoB-lipoprotein assembly will be determined using enterocytes isolated from MTPfl/flMxICre mice treated with pIpC to induce conditional deletion of the gene. The participation of cholesterol efflux will be studied using ABCA1, apoAl and apoAIV null mice. The role of intracellular HDL assembly in cholesterol transport will be evaluated using apoAIV-/-,ABCA1-/- and apoAl-/- ,ABCA1-/- double knockout mice. Contribution of these proteins in total cholesterol absorption will be studied in knockout mice fed chow and Western diets. Studies proposed in this application will result in the discovery of a new function for MTP in cholesterol esterification. In addition, these studies will identify, characterize and establish the importance of various candidate proteins and different pathways in the secretion of cholesterol by enterocytes.

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