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The normal heart loves fat. About 70 percent of the fuel burned by the heart muscle comes from lipids, while the rest comes from glucose.

But relying too much on fat is associated with heart disease. When the cardiac muscle burns more than 70 percent fat, as it does in diabetes or obesity, the heart enlarges and can't pump blood efficiently. The functional changes result from changes in fat processing inside the cells.

Now Columbia researchers have found the first conclusive evidence that changes in cellular fat uptake also can cause heart disease. The new finding could lead to a drug to prevent fat uptake and the toxic effects of fat on cardiac muscle cells. The research, by Dr. Ira Goldberg, chief of the Division of Preventative Medicine & Nutrition and professor of medicine, and his colleagues, is published in the February Journal of Clinical Investigation.

When Dr. Goldberg and his postdoctoral researcher Dr. Hiroaki Yagyu began the study, they were not looking for a new heart disease model. Instead, they were testing the dogma concerning an enzyme that breaks triglycerides into fatty acids. The enzyme—lipoprotein lipase—is made by muscle cells in the heart and displayed on the outer surface of the cells. But it is thought that the enzyme only works after it travels from the muscle cell to nearby blood vessels. In the blood vessels, the enzyme encounters the triglycerides and breaks them down into fatty acids. The fatty acids then make their way into the heart muscle cells where they are used for fuel.

The researchers questioned whether the enzyme was truly inactive when displayed in the heart cells. So they made a transgenic mouse that expressed excessive amounts of the human lipase that was anchored only on heart cells to see if the cardiac enzyme worked.

At first, Dr. Goldberg says, the results seemed to show that dogma is correct because the cardiac enzyme had no influence on fatty acid levels in the blood.

When the researchers used radioactively labeled fats to track the fatty acids, they found the dogma was wrong—the heart cells acquired radioactive fatty acids that could have only come from lipase activity on the heart.

The researchers then found out how important the cardiac lipase may be. As graduate student Ayanna Augustus weighed the hearts, she noticed a difference between the transgenics and the normal controls. "The transgenic hearts were much heavier," Dr. Goldberg says. "That's when we realized the excess enzymes on the heart were causing heart disease."

Analysis of the transgenic hearts showed they were enlarged and not able to pump normally; ultimately, those mice lived shorter lives.

Dr. Goldberg's new finding shows that it is not just defective fat metabolism inside the cell that can lead to heart disease, but also defects in the amount of fat delivered into the cell.

The finding also may be relevant to the heart disease associated with obesity and diabetes in people, in which excess fat uptake by heart cells is suspected to contribute. The researchers are now trying to find ways to reduce the amount of fatty acids delivered to the heart.

"Having a model of excess fat uptake now gives us an opportunity to ask how we can correct the problem," Dr. Goldberg says.

The study was sponsored by the National Heart, Lung, and Blood Institute and the Japan Health Foundation.


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