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or decades, nutritionists have known that a traditional Mediterranean diet high in grains, legumes, fish, and unsaturated fats reduces the risk of heart disease compared with a Western diet, which is high in processed foods and saturated fats.

Now Columbia Health Sciences researchers have new evidence for why oleic acid, an unsaturated fat found in the olive oil used in Mediterranean foods, may contribute to the lessened cardiovascular risk.

Dr. Tilla Worgall, assistant professor of pediatrics in the Institute of Human Nutrition, and Dr. Richard Deckelbaum, director of the Institute of Human Nutrition, Robert R. Williams Professor of Nutrition, and professor of pediatrics, have found that the protective effect of unsaturated fatty acids may work to lower cholesterol partly through the fatty acid’s effect on ceramide. Ceramide is a component of sphingomyelin, a lipid present in cell membranes.

The discovery of a new role for ceramide started several years ago when the Columbia scientists found that unsaturated fatty acids inhibit a transcription factor that increases cholesterol manufacture inside a cell. When active, the molecule—called SREBP, for sterol regulatory element binding protein—binds to the cell’s SRE promoter and turns on genes for cholesterol synthesis. When inactive, the cell makes little of its own cholesterol.

In the new research, published in the Feb. 8 Journal of Biological Chemistry, Dr. Worgall reveals how unsaturated fatty acids increase levels of ceramide, which lowers both SREBP activity and cholesterol manufacture inside the cell.

In the study, Dr. Worgall first determined if oleic acid acted on sphingomyelin to release cholesterol in cultured cells because other research showed that cholesterol could lower SREBP activity. Sphingomyelin tightly holds cholesterol within the bilipid cell membrane. After radioactively labeling the cells’ sphingomyelin, she found that fatty acid-treated cells had less sphingomyelin in their membranes than untreated cells. As sphingomyelin fell apart, she found that cholesterol and ceramide became free from the cell membrane.

Although findings from other researchers showed that cholesterol alone could inhibit the activity of SREBP, Dr. Worgall wanted to know if ceramide on its own could reduce the activity of SREBP. So she added ceramide to the cells at the same time she added a molecule that blocked the release of cholesterol from the cell membrane. Ceramide was able to inhibit SREBP activity by itself. And surprisingly, the ceramide seems to have a greater inhibitory effect in turning off cholesterol production in the cell in response to fatty acids than the cholesterol released from the membrane.

To monitor SREBP activity, Dr. Worgall used CHO cell lines with a luciferase reporter gene hooked up to the SRE promoter.

Dr. Worgall says the ceramide pathway, besides possibly explaining how unsaturated fatty acids in olive oil protect the heart, may be good news for people who have metabolic disorders. “In late-onset diabetes, SREBP is massively turned on even though cholesterol can be high,” she says. “The ceramide pathway may open the way to a new class of drugs to control SREBP and reduce the high cholesterol and triglycerides that can lead to atherosclerosis in diabetics.”



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