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Triglyceride metabolism: Genetics, smoking and heart disease

Institution: J. David Gladstone Institutes
Investigator(s): Ugur Hodoglugil, M.D., Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12FT-0226 Award: $75,438
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Coronary heart disease (CHD) is the leading cause of death in the United States and the world. The most common cause of CHD is atherosclerosis, which is characterized by the accumulation oflipids in the arterial wall, leading to a narrowing of the lumen and a heart attack. Several risk factors have been identified, including plasma lipid abnormalities, such as elevated cholesterol or triglycerides, and environmental or lifestyle factors, such as smoking. Elevated plasma triglycerides can represent an independent risk factor or be associated with low levels of high density lipoprotein cholesterol (HDL-C). Smoking accentuates the detrimental effects of various risk factors and is also associated with elevated triglyceride levels. A better understanding of the atherosclerotic process, including the factors that regulate plasma triglycerides, may lead to novel ways to control plasma lipids and thus counteract the harmful effects of smoking on the atherosclerotic process.

The present study is designed to understand the role of the microsomal triglyceride transfer protein(MTP) on plasma triglyceride levels. This protein, which is produced in the liver, is critical for transferring lipids, including triglycerides, to the precursors of plasma very low density lipoprotein (VLDL) particles. VLDL are triglyceride-rich lipoproteins. In a large population study we have shown that genetic variation in the structure of the MTP gene can be associated with high plasma triglyceride levels. Importantly, we have shown that these genetic variations in MTP can interact with apolipoprotein (apo) E isoform–specific genotypes to enhance further plasma triglyceride levels. Previously, it was shown that the apoE4 isoform was associated with elevated triglycerides and thus the interaction between apoE4 and MTP could help to explain this observation. In addition, we have found that genetic variations in MTP and smoking interact to cause high triglyceride levels. Therefore, understanding how various factors, including MTP and apoE, interact could lead to important new data related to smoking and CHD.

Specific Aim 1 is to generate transgenic mice expressing low and high levels of MTP activity in their livers. This will allow us to understand how MTP regulates triglyceride and VLDL levels. In Specific Aim 2 we will cross the human MTP transgenic mice with either apoE3- or apoE4-expressing mice to determine the effect of apoE phenotype on MTP-modulated triglyceride metabolism. Plasma lipids and lipoproteins, including VLDL-triglyceride and apoB production, will be studied in these animal models.