The long term objective is to understand the molecular mechanisms involved in the biosynthesis of apoB48-containing lipoproteins. Our working model is that in post-prandial state apoB48-containing lipoproteins are synthesized first as HDL-like primordial lipoproteins and at a later stage the core of these particles is increased to accommodate large amounts of neutral lipids. We hypothesize that the coordinate induction of triglyceride and apoAIV synthesis results in the assembly and secretion of larger chylomicrons. To examine this hypothesis, we will: 1. Develop cell culture that can synthesize large quantities of apoB48- containing lipoproteins and study the effect of increased triglyceride synthesis on the assembly and secretion of these particles. 2. a) Analyze the role of apoAIV in the stabilization of the surface of intracellular nascent particles by expressing apoAIV in Caco-2 cells, cotransfected or not with apoB48, and studying the increase in size of the secreted lipoproteins and b) study the coordinate effects of increased neutral lipid and apoAIV synthesis on lipoprotein assembly and secretion. 3. Determine the rates of intracellular degradation and secretion of apoB48 by pulse-chase analysis of transfected cell lines, perform control experiments to eliminate the possibilities of extracellular degradation, uptake and sequestration of nascent particles and examine the effect of neutral lipid synthesis in conjunction with the overexpression of apoAIV on the rates of intracellular degradation and secretion of apoB48. These studies will provide information about the role of apoAIV in the stabilization of nascent particles and the effect of increased neutral lipid and apoAIV synthesis on intracellular degradation of apoB48. Such information will serve as the groundwork for in vivo studies to modulate lipoprotein secretion in the context of disorders such as hypertriglyceridemia, hypercholesterolemia, and atherosclerosis. The cell lines developed will be valuable in the study of intracellular mechanisms of lipoprotein assembly.

Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Pan, Xiaoyue; Schwartz, Gary J; Hussain, M Mahmood (2018) Oleoylethanolamide differentially regulates glycerolipid synthesis and lipoprotein secretion in intestine and liver. J Lipid Res 59:2349-2359
Irani, Sara; Pan, Xiaoyue; Peck, Bailey C E et al. (2016) MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice. J Biol Chem 291:18397-409
Khalifeh-Soltani, Amin; Gupta, Deepti; Ha, Arnold et al. (2016) Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity. JCI Insight 1:e87418
Hsieh, Joanne; Koseki, Masahiro; Molusky, Matthew M et al. (2016) TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature 535:303-7
Walsh, Meghan T; Iqbal, Jahangir; Josekutty, Joby et al. (2015) Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal ?-Barrel in Microsomal Triglyceride Transfer Protein Function. Circ Cardiovasc Genet 8:677-87
Iqbal, Jahangir; Boutjdir, Mohamed; Rudel, Lawrence L et al. (2014) Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs. J Lipid Res 55:2261-75
Dikkers, Arne; Annema, Wijtske; de Boer, Jan Freark et al. (2014) Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice. J Lipid Res 55:816-25
Hussain, M Mahmood (2014) Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol 25:200-6
Khatun, Irani; Walsh, Meghan T; Hussain, M Mahmood (2013) Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. J Lipid Res 54:1541-9
Iqbal, Jahangir; Parks, John S; Hussain, M Mahmood (2013) Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice. J Biol Chem 288:30432-44

Showing the most recent 10 out of 23 publications