How does cardiac fuel metabolism influence heart disease?
Abstracts
Initial Award Abstract |
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Cigarette smoking is well established as a risk factor in atherosclerotic coronary artery disease and myocardial infarction, as well as for two common results of myocardial infarction, sudden cardiac death and congestive heart failure. More cigarette smokers die from coronary heart disease than from lung diseases, and the morbidity and treatment costs for coronary heart disease are extremely high. It has been widely assumed that lipoproteins (fat-transporting proteins in blood) are secreted only by the intestine and liver. We recently demonstrated that the heart is a lipoprotein secreting organ. The reason why the heart makes and secretes lipoproteins is unknown, but I have hypothesized that the heart may make and export lipoproteins to unload surplus cellular fats (or lipids), particularly triglycerides, that are not immediately required for fuel. I believe that lipoprotein secretion by the heart represents a highly significant, provocative, and novel research topic, both for cardiac fuel metabolism (i.e., the utilization of fat as an energy source for heart muscle) and for coronary heart disease. I plan to further investigate lipoprotein secretion by the heart using a wide range of experimental techniques. The size and density of secreted lipoproteins, which may relate to how they are utilized and their roles in heart disease, will also be assessed using both heart tissue ex vivo and primary cultures of mouse neonatal cardiac muscle cells.
I will also test the hypothesis that the secretion of apo B (another plasma protein) by the heart might play an important role in exporting excess lipids, particularly triglycerides, from specific heart muscle cell types (cardiac myocytes). First, I will utilize mice that lack lipoprotein synthesis in the heart and then determine whether the absence of lipoprotein secretion by the heart causes the cardiac myocytes to accumulate increased amounts of fat within the cells. Second, the possibility that excessive production of human apo B in the hearts of transgenic mice leads to diminished stores of fats within cardiac muscle cells will be examined. I will determine whether overexpression of lipoproteins in the heart reduces myocardial triglyceride accumulation under various experimental conditions. For example, does cigarette smoke and/or nicotine raise plasma levels of free fatty acids, and do elevated levels of plasma fatty acids increase intracellular stores of triglycerides in cardiac muscle? I will determine whether overexpression of apo B in the heart limits the amount of triglyceride accumulation in the setting of various experimental interventions that increase plasma fatty acid levels and promote fat accumulation in heart muscle. Results of these studies will provide insight into possible pathways by which cardiac fuel metabolism influences human susceptibility to coronary heart disease. |
Final Report |
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Cigarette smoking is a well-established risk factor for atherosclerotic coronary artery disease and myocardial infarction, as well as for two common results of myocardial infarction, sudden cardiac death and congestive heart failure from “ischemic” cardiomyopathy. More cigarette smokers die from coronary heart disease than from lung diseases, and the morbidity and cost of treatment for coronary heart disease are extremely high.
In experimental animals, smoking increases triglyceride stores within cardiac myocytes. In the setting of any advanced form of heart disease, cardiac muscle from patients with congestive heart failure stops using fatty acids as fuel and reverts to the use of glucose. Smoking causes degenerative changes in cardiac muscle mitochondria, and mitochondrial disorders in turn increase myocardial triglyceride accumulation. In fact, patients with certain inherited mitochondrial disorders are prone to developing fatty heart and sudden cardiac death. Why the heart synthesizes and secretes lipoproteins is unknown.
I hypothesized that the heart uses lipoprotein synthesis to unload surplus cellular lipids, particularly triglycerides that are not immediately required for fuel. Thus far, I have made progress in determining that long-chain acylCoA dehydrogenase mice expressing human apo-B (LCAD–/–HuBTg+/0) and HuBTg+/0 mice have smaller amounts of stored triglycerides in the heart than LCAD and nontransgenic mice, respectively. Both transgenic models accumulate triglycerides in the heart after fasting and have higher levels of apo-B expression in the heart. This finding is the first that supports a role for lipoprotein secretion in exporting surplus triglyceride stores from cardiomyocytes. I also established primary cell culture of cardiomyocytes from 2–5-day-old pups of HuBTg and nontransgenic mice and used those cells for oleic acid and 35S-methionine labeling studies. These experiments showed that cardiomyocytes from HuBTg mice secreted a higher level of triglycerides than those from nontransgenic mice. In addition, I demonstrated that isolated perfused hearts secrete triglycerides and that hearts from HuBTg mice secrete a higher amount of triglycerides than hearts from nontransgenic mice.
Understanding all aspects of apo-B biology is fundamentally important for understanding atherosclerosis and for developing pharmaceutical strategies to prevent or treat it. Cigarette smoking and high levels of apo-B-containing lipoproteins in the plasma are inextricably linked in causing atherosclerosis and coronary heart disease. |
Publications
| Analysis of the role of microsomal triglyceride transfer protein in the liver with tissue-specific knockout mice |
| Periodical: Journal of Clinical Investigation |
Index Medicus: |
| Authors: Raabe M, Veniant M, Sullivan MA, et al |
ART |
| Yr: 1999 |
Vol: 103 |
Nbr: |
Abs: |
Pg: 1287-1298 |
| Lipoproteins containing apolipoprotein B 100 are secreted by the heart |
| Periodical: Trends in Cardiovascular Medicine |
Index Medicus: |
| Authors: Veniant M, Nielsen LB, Boren J, Young SG |
ART |
| Yr: 1999 |
Vol: 9 |
Nbr: |
Abs: |
Pg: 103-107 |
| A deficiency of microsomal triclyceride transfer protein reduces apolipoprotein B secretion |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Leung GK, Veniant M, Kim SK, et al |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 7515-7520 |
| Analysis of the role of microsomal triglyceride transfer protein in the liver with tissue-specific knockout mice |
| Periodical: Journal of Clinical Investigation |
Index Medicus: |
| Authors: Raabe M, Veniant M, Sullivan MA, et al |
ART |
| Yr: 1999 |
Vol: 103 |
Nbr: |
Abs: |
Pg: 1287-1298 |
| Lipoproteins containing apolipoprotein B 100 are secreted by the heart |
| Periodical: Trends in Cardiovascular Medicine |
Index Medicus: |
| Authors: Veniant M, Nielsen LB, Boren J, Young SG |
ART |
| Yr: 1999 |
Vol: 9 |
Nbr: |
Abs: |
Pg: 103-107 |
| A deficiency of microsomal triclyceride transfer protein reduces apolipoprotein B secretion |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Leung GK, Veniant M, Kim SK, et al |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 7515-7520 |
