Scientists at the Whitehead Institute for Biomedical Research and Millennium Pharmaceuticals, Inc. have identified a protein in the small intestine that plays a key role in the uptake of dietary fat in the body. In the September 24 issue of Molecular Cell, the scientists report that the protein, called fatty acid transporter protein-4 (FATP4), may constitute a novel target for anti-obesity therapy in humans.
In this study, scientists in the lab of Professor Harvey Lodish (a professor of biology and Whitehead member) and their colleagues at Millennium found that FATP4 is present at high levels in the cells that line the villi, the tiny finger-like projections in the small intestines. These cells are responsible for transporting nutrients such as sugars and fatty acids into the body.
When the scientists decreased by 60 percent the level of FATP4 in the intestinal cells of mice, it resulted in a corresponding decrease in the uptake of fatty acids from the intestines. When they caused FATP4 to be expressed in cells that do not normally make this protein, these cells increased their uptake of fatty acids in a manner that resembled that of normal cells.
"Our data suggest that if we could design a drug that blocks this uptake, even by 60 percent, it could drastically reduce the fat uptake by the small intestine. This means that more than half of the dietary fat would never enter the body and would be removed from the body as waste," Professor Lodish said.
Fats, mainly in the form of triglycerides, make up more than 40 percent of the calories in the American diet. Too much fat -- obesity -- affects more than 50 million Americans and is linked to many major causes of death in the US, including hypertension, diabetes and cancer.
"Finding a drug that could reduce the fat intake in morbidly obese people could have a major impact on public health," said Dr. Andreas Stahl of the Whitehead Institute, first author on the paper. Currently, people resort to crash diets or fat substitutes to combat obesity, and the one FDA approved anti-obesity drug in the market has shown only modest success. "We hope that finding a drug that blocks FATP4 activity may provide a better, or at least an alternative, treatment strategy for obesity," said Professor Lodish.
FAT METABOLISM
In normal human beings, less than 5 percent of the dietary fat consumed is excreted from the body. The rest of the fats we eat are metabolized into glycerol and fatty acids. The fatty acids are then absorbed by cells lining the intestinal villi and converted into so called "chylomicron" particles that enter the lymphatic system and eventually are stored as "fat" in convenient places like hips and thighs.
Until recently, scientists assumed that fatty acids -- which are the main source of energy for heart, liver and fat cells -- simply diffused across the plasma membranes of cells, unlike glucose and other small molecules that require specific transport proteins. However, a few years ago, scientists in the Lodish lab found a protein called FATP (Fatty Acid Transport Protein) that plays a key role in transporting a vital fatty acid nutrient into heart muscle; this protein was the first known fatty acid transporter.
Since then, the Lodish lab has identified additional FATP genes -- five in mice and six in humans. Scientists now believe that in addition to a small amount of diffusion, heart, liver, muscle and fat cells also use a transport protein to move fatty acids across the cell membrane. The scientists also found that these transporters have a signature sequence in their genes that makes it easy to identify them.
Most recently, Dr. Stahl and David Hirsch of the Whitehead and colleagues at Millennium Pharmaceuticals and the Lodish lab found that one particular member of this family of transporters -- FATP4, present in both mice and humans -- is expressed at high levels in cells that line the small intestine. They suspected that this transporter may play a role in uptake of fat, and this led to the study reported this week.
Dietary fat is converted more readily to body fat than is carbohydrate or protein and is the easiest to store in the body, say scientists. FATP4 facilitates this process by being the main gatekeeper that enables fat uptake into the body. If a drug could inhibit this process, it could result in a viable treatment for obesity.
Scientists plan to explore this next step in the coming months. They plan to continue studies to find a candidate that inhibits FATP4 and then later conduct experiments in animals to test the viability of the candidate.
The Molecular Cell study was funded by a grant from the National Heart, Lung and Blood Institute.
Other Whitehead-affiliated authors of the paper are Nicki Watson, Shraddha Patel and Mariana Kotler.
A version of this article appeared in MIT Tech Talk on September 29, 1999.
