Having too much fat can be a serious problem. It contributes to obesity, diabetes, and heart disease. For years, scientists have peered through their microscopes at small round organelles found in many types of cells. Everyone knew they were filled with lipids or fats, but as important as those lipid droplets are to human health, no one knows exactly how they are formed or what controls their size or numbers. A new study led by Yi Guo and Robert V. Farese, Jr., in the Gladstone Institute of Cardiovascular Disease, now gives some insights into this fundamental biological problem.
“For some time, we have been studying the enzymes that make fats, and we know a lot about these enzymes,” said Dr. Farese, senior investigator. “But clearly, we need to know a lot more about how these fats are stored in cells. Very little is known about the processes that occur after the enzymes synthesize the fats. Such an understanding is crucial to understanding diseases of fat excess.”
To identify novel genes involved in fat storage, the laboratories of Drs. Farese and Peter Walter (University of California, San Francisco) initiated a major discovery project, in which they used RNAi screens to individually inactivate all the genes in cells from fruit flies. Basic cellular processes in humans are highly conserved in cells from fruit flies, so the results should mostly be applicable to human biology. Drs. Yi Guo and Tobias Walther, from the Farese and Walter laboratories, respectively, completed the initial survey, and identified the genes that have the most striking effects on fat storage.
Surprisingly, they found that ~1.5% of all genes function in lipid-droplet formation and regulation. These genes proved to be determinants of the size, numbers, and physical locations of lipid droplets in cells. Interestingly, when the individual genes were deleted, the results for related genes often gave similar results, suggesting the identification of novel pathways that regulate fat storage in cells. In their first study, the group studied how the loss of specific genes caused cells with large fat droplets and cells with more dispersed droplets.
The most interesting genes will be advanced into functional studies in flies or mice. These new studies promise two major outcomes: significant advances in understanding the processes that regulate fat metabolism in cells and novel therapeutic targets for treating diseases such as obesity and diabetes.
“With the screens under way, the work turns now to many fascinating questions,” said Dr. Farese. “How are lipid droplets formed? What regulates their size, numbers, and cellular locations? Do they help to traffic lipids within the cell? How does this cell biology relate to physiology and disease? These are early days in this area of biology, and the field is wide open.”
Illustration: Microsoft clipart.
Gladstone Institutes of Cardiovascular Disease News Release (05/21/08)
Medical News Today (05/22/08)
Science Daily (05/24/08)
Abstract (Nature; 453, 657-661 (05/29/08))