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Chemical Genomics Screen Uncovers Clues to Fat Storage

Chemical Genomics: Robot
High-throughput screening of small chemicals conducted at the National Institutes of Health (NIH) Chemical Genomics Center (NCGC), administered by the National Human Genome Research Institute (NHGRI), has helped to provide new insights into the way our bodies store fat. Such knowledge may prove valuable in efforts to reduce obesity and treat metabolic disorders.

In a study published in the Nov. 25, 2008 issue of PLoS Biology, a team from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the University of Maryland, Baltimore, and NCGC identified a cellular pathway that regulates fat storage and showed that interrupting the pathway boosts the amount of fat stored by human cells.

Building upon their colleagues' initial work in fruit flies and mice, Douglas S. Auld, Ph.D., said his group at NCGC used quantitative, high-throughput technology to screen thousands of chemical compounds for their potential to disrupt the fat storage pathway. Their screening identified two such compounds, Exo1 and Brefeldin A, both of which are known to play a role in protein transport, but have not been previously linked to fat storage. Researchers can now use the compounds identified by NCGC as probes to gain a more detailed understanding of how fats are stored within cells.

Fats, also known as lipids, are a major source of energy, and humans must consume a certain amount of fat daily to remain healthy. Excess fat is stored in the cells of the body by converting the fatty acids found in food into droplets. These droplets then remain in reserve inside the cell until the energy contained is required. The processes that create droplets and break them down again have previously been poorly understood.

The new study focused on two proteins, dubbed Coat Protein Complex I (COPI) and PAT, that are found in the cells of many organisms, from fruit flies to mice to humans. PAT, which sits on the outside of lipid droplets, was already known to be essential to lipid storage. However, researchers were surprised to discover that the COPI transport complex has a separate role in trafficking cellular components.

In fact, the new study shows that PAT is regulated by COPI. Specifically, COPI acts to change the composition of the lipid droplet surface, attracting an enzyme called ATGL, which causes the droplet to be broken down. Therefore, COPI reduces the amount of lipid stored in a cell, releasing energy for movement and other activities. COPI acts to reduce the amount of PAT at the lipid droplet surface. The absence of PAT in mice or flies leads to lean animals, whereas greater than average expression of the protein leads to obese animals.

The NIH researchers originally used a microscope-based assay system to perform RNA interference (RNAi) screening to arrive at the finding. This assay was optimized by the NCGC, where laser-scanning microplate cytometery was used to enable ultra-high-throughput screening of small molecule libraries. Those results supported and expanded upon the finding of an association between lipid storage and the COPI protein complex. "This study illustrates how coupling small-molecule screening and RNAi studies can lead to the discovery of new pathways, along with the creation of valuable tools to further elucidate important biological pathways," Dr. Auld said.

The NIH Chemical Genomics Centre (NCGC) is an ultra-high-throughput screening and chemistry center that discovers chemical probes of gene and cell functions to be used as research tools for the elucidation of biological functions, or as starting points to the development of new therapeutics for rare and neglected diseases. The NCGC collaborates with over 100 investigators from academic, foundation and biopharmaceutical laboratories throughout the world, utilizing its unique quantitative high-throughput screening (qHTS) paradigm and innovative cheminformatics and medicinal chemistry platforms to produce new insights in chemical biology and general principles of chemical interactions with living systems.

To read the full study, go to PLoS Biology at: COPI Complex Is a Regulator of Lipid Homeostasis [biology.plosjournals.org]

Last updated: May 08, 2012