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Apolipoprotein E: remnant metabolism and atherogenesis

Institution: J. David Gladstone Institutes
Investigator(s): Yadong Huang, M.D., Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0130 Award: $793,474
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking is a major risk factor for cardiovascular disease. In smokers, the incidence of cardiovascular disease is more than twofold higher than in nonsmokers, and in smokers with high cholesterol the risk is sixfold higher. One of the major effects of cigarette smoking is to raise the level of cholesterol in the blood. High cholesterol is unquestionably a risk factor for the development of heart disease. Two of the major cholesterol transporting components in human blood—called low-density lipoproteins and remnant lipoproteins—promote the development of heart disease and both are increased in smokers.

Remnant lipoproteins are complexes of fat and proteins. One of the proteins, called apolipoprotein (apo) E, is a major component of remnant lipoproteins. By interacting with liver cells, apoE promotes removal of these dangerous lipoproteins from the blood.

An initial step of remnant lipoprotein removal by the liver involves the interaction of apoE with a group of sticky molecules on the cell surface, referred to by acronym HSPG. A major goal of the proposed study is to establish the importance of the HSPG pathway in apoE-mediated removal of remnant lipoproteins. To accomplish this, we will overexpress HSPG in rat liver cells in culture and in transgenic mice and study its effect on remnant lipoproteins. Another major goal of the project is to establish several transgenic mouse lines expressing apoE into which mutations have been introduced that might affect remnant lipoprotein removal. Analysis of remnant lipoproteins and their ability to cause heart disease in these transgenic mice will improve our understanding of the role of apoE in remnant lipoprotein removal and in the development of heart disease. The understanding derived from the proposed studies holds the potential for leading to new therapies for human heart disease.
Publications

Pathogenesis of type III hyperlipoproteinemia: lessons from transgenic animal studies
Periodical: Atherosclerosis Index Medicus:
Authors: Huang Y, Liu XQ, Rall SC, Mahley RW ABS
Yr: 2000 Vol: 150 Nbr: Suppl 1 Abs: S6 Pg:

Apolipoprotein (apo) E modulates hepatic very low density lipoprotein (VLDL) assembly and secretion
Periodical: Atherosclerosis Index Medicus:
Authors: Huang Y, Brecht WJ, Liu XQ, et al ABS
Yr: 2000 Vol: 151 Nbr: 1 Abs: 158 Pg:

Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and imparing VLDL lipolysis.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Huang Y, Ji ZS, Brecht WJ, Rall SC, Taylor JM, and Mahley RW ART
Yr: 1999 Vol: 19 Nbr: Abs: Pg: 2952 - 2959

Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): Questions, quandaries, and paradoxes.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Mahley RW, Huang Y, and Rall SC ART
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 1933 - 1949

Overexpression of apolipoprotein E stimulates synthesis and mobilization of triglycerides to the endoplasmic reticulum in rat hepatoma cells (McA-RH7777).
Periodical: Circulation Index Medicus:
Authors: Huang Y, Brecht WJ Liu XQ, Rall SC, and Mahley RW ABS
Yr: 1999 Vol: 100 Nbr: Abs: Pg: 1 - 686

Lipoprotein preference of apolipoprotein E with cysteine 158 determines recessive or dominant mode of transmission of type III hyperlipoproenemia.
Periodical: Circulation Index Medicus:
Authors: Huang Y, Liu XQ, Rall SC, and Mahley RW ABS
Yr: 2000 Vol: 102 Nbr: Abs: Pg: 1 - 146