Breakthrough In Understanding The Biology Of Fat -- UCSF/Gladstone Scientists Discover Gene For Key Enzyme

Now a research team led by scientists at the Gladstone Institute of Cardiovascular Disease and the University of California San Francisco has discovered a major piece in the puzzle of how our bodies build and regulate fat.

The researchers have found a gene that encodes DGAT, a key enzyme in fat production. Their study results are published today (October 27) in The Proceedings of the National Academy of Sciences USA.

Known officially as acyl CoA:diacylglycerol acyltransferase, the DGAT enzyme joins other smaller molecules to produce, or synthesize, a specific group of fats called triglycerides. Triglycerides are one of the major lipids (fats) found in the bloodstream, and they constitute more than 95 percent of the fat stored in the adipose (fat) tissue of mammals, thereby serving as the major source of stored energy.

"This finding has implications for many aspects of biology," said Robert V. Farese, Jr., MD, Gladstone scientist and UCSF assistant professor of medicine, who is principal investigator of the study. "Identifying a gene encoding DGAT gives us a valuable tool to evaluate this enzyme and to explore triglyceride synthesis as it relates to human energy cycles, obesity, and cardiovascular disease. The finding also may have implications for potential development of drug therapies aimed at lowering triglyceride levels or treating obesity."

Because of its role in fat synthesis and energy storage, DGAT is thought to be a major player in the absorption of fats in the intestine, regulation of triglyceride concentrations in blood plasma, fat storage in fat cells, energy metabolism in muscle cells, and triglyceride synthesis involved in milk and egg production, according to Farese.

"In future research efforts we want to focus on determining the role that DGAT plays in these processes in mammals," he said.

DGAT also plays an important role in the synthesis of seed oils, such as canola oil, in plants, so a greater understanding of the enzyme has potential implications in agricultural science, he added.

Although scientists have known that this important enzyme existed for several decades, DGAT proved difficult to isolate in its pure form because it is a protein that normally is associated with membranes and resists being pulled away from the lipid-rich membrane environment, Farese said.

He and his colleagues took advantage of computer-based searching to "find" DGAT. The team used the known DNA sequence of a related enzyme--called ACAT--involved in cholesterol metabolism to screen computer databases containing snippets of human and mouse genes.

"Serendipitously, we found a "hit" for a sequence from a gene that appeared to be a "cousin" of the ACAT gene. Then our group, led by Sylvaine Cases, PhD, went on to isolate the whole gene for this sequence from mouse tissue and to determine that it coded for a DGAT enzyme," Farese said.

The researchers also were able to use the newly discovered DNA sequence to learn about DGAT. For example, they found large amounts of DGAT gene expression in the intestine and in fat tissue--indicating that these mouse tissues are where significant amounts of DGAT are made. "These sites are consistent with a role for DGAT in fat metabolism," said Cases, a postdoctoral fellow who is first author of the study.

In addition to Farese and Cases, study co-investigators are postdoctoral fellows Steven Smith, PhD, and Sabine Novak, PhD, and research associates Heather Myers and Eric Sande, all of the Gladstone Institute of Cardiovascular Disease; Yao-Wu Zheng, PhD, of the UCSF Cardiovascular Research Institute; Sandra Erickson, PhD, and Steven Lear of the San Francisco Veterans Affairs Medical Center; Colin Collins of the Lawrence Berkeley National Laboratory; and Carrie Welch, PhD, and Aldons Lusis, PhD, of UCLA.

The research was supported by the J. David Gladstone Institutes, National Institutes of Health, American Heart Association, and Department of Veterans Affairs.

The Gladstone Institute of Cardiovascular Disease focuses on the study of cholesterol and lipid metabolism and their impacts on cardiovascular disease.

The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF and named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing personal interest in medical education.