Principal investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research at Washington University School of Medicine, first identified the protein, CD36, that facilitates the uptake of fatty acids. The protein is located on the surface of cells and distributed in many tissues, including fat cells, the digestive tract, heart tissue and skeletal muscle tissue.
Her studies have shown that the intestine makes large amounts of CD36, and that it is important to the absorption of fatty acids. Initially when she compared normal mice that made the protein to genetically altered mice lacking CD36, she couldn't find any net difference in their fat absorption.
But the new study, reported in the July 6 issue of the Journal of Biological Chemistry, reveals the reason it was not possible to identify a difference. Apparently, the intestine has some built-in redundancy. Normally, CD36 absorbs fatty acids in the upper, or proximal part of the intestine, but when it is absent, lower, more distal, sections of the intestine compensate and absorb the fat.
"We think of the intestine as a single organ, but it's really made up of distinct areas that are so specialized it's almost like several organs," Abumrad says. "The fat that is not absorbed in the proximal areas ends up being bumped into the distal intestine where different systems absorb it,"
Abumrad and her colleagues, including first author Fatiha Nassir, Ph.D., research assistant professor in the Division of Gerontology and Nutritional Science, believe that targeting the upper part of the intestine and interfering with normal CD36 function might be a useful tool in weight loss. The team found that animals that could not make CD36 absorbed fat less efficiently, and as a result they tended to eat less of it.
"And the most exciting part for us right now is the fact that these things may apply to humans," Abumrad says. "Humans with mutations in the gene that makes CD36 don't seem to process fat normally either."
She learned from the mice that when fatty acids and cholesterol are not absorbed in the proximal part of the intestine, as normally occurs, the distal intestine packages those fats very differently.
"The proximal intestine makes molecular packages called chylomicrons," she says. "These bundles that contain lipids and proteins transport these molecules from the intestine to other parts of the body. CD36, which is abundant in the proximal intestine, turns out to play a role both in absorbing fatty acids and cholesterol and in packaging these lipids into chylomicron bundles that facilitate their use throughout the body."
When no CD36 was present in the genetically altered mice in Abumrad's study, the lipids were absorbed more slowly since they had to travel to lower, more distal parts of the intestine. And they also were packaged differently. Rather than being bundled into chylomicrons, the lipids were released as parts of smaller particles that are not as easily absorbed by other tissues as the chylomicrons.
For years, Abumrad has studied how CD36 modulates the acute and chronic responses of muscle and fat cells to energy fluctuations and other stresses. Her goal is to translate her findings from rodents into humans, where variations in the CD36 gene are common.
"There is evidence that people have different amounts of CD36 and that mutations in the gene are quite common," she says. "Those variations are associated with abnormalities of blood lipids, with high levels of fatty acids in the blood, abnormal blood triglycerides and increased risk of diabetes-associated heart disease. It's clear that some of us have different amounts of this protein in different tissues, and some individuals don't have any of it."
Although scientists in Abumrad's laboratory think it may be possible eventually to help people lose weight by interfering with the CD36 protein, they first want to learn more from the mouse. Currently, they work with mice that cannot make CD36 anywhere in their bodies. But because the protein also operates in heart tissue and skeletal muscle, disabling CD36 everywhere can have detrimental effects. So the team is working to develop a new kind of mutant mouse, one that can make CD36 everywhere except in the intestine.
"If we find that such a mouse still has delayed absorption of fatty acids and cholesterol and ends up eating less fat, we'll have more evidence that this might be a good approach to use in humans," she says. "Block the function of the protein in the intestine, absorb fewer lipids, and since your absorption is delayed, you don't feel as hungry and you eat less."
But until such a mouse is developed, Abumrad's team cannot be certain that blocking the effects of CD36 in the intestine might not also have harmful effects. Interfering with CD36 function to absorb less fat is not necessarily a good thing if it causes problems in the heart, the liver or elsewhere in the body.
Jim Dryden | EurekAlert!
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