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

October 27, 1998

Not only do Americans consume a lot of fat, they are consumed by how to control it.

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.
-end-
Note To The Media: Copies of the PNAS paper are available from the National Academy of Sciences News and Public Information Office at (202)334-2138. Reporters who would like to interview Robert Farese, Jr., MD, study principal investigator, can reach him directly at (415)695-3759.
-end-


University of California - San Francisco

Related Cardiovascular Disease Articles from Brightsurf:

Changes by income level in cardiovascular disease in US
Researchers examined changes in how common cardiovascular disease was in the highest-income earners compared with the rest of the population in the United States between 1999 and 2016.

Fighting cardiovascular disease with acne drug
Researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg and Stanford University have found the cause of dilated cardiomyopathy - a leading cause of heart failure - and identified a potential treatment for it: a drug already used to treat acne.

A talk with your GP may prevent cardiovascular disease
Having a general practitioner (GP) who is trained in motivational interviewing may reduce your risk of getting cardiovascular disease.

Dilemma of COVID-19, aging and cardiovascular disease
Whether individuals should continue to take angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the context of coronavirus disease 2019 (COVID-19) is discussed in this article.

Air pollution linked to dementia and cardiovascular disease
People continuously exposed to air pollution are at increased risk of dementia, especially if they also suffer from cardiovascular diseases, according to a study at Karolinska Institutet in Sweden published in the journal JAMA Neurology.

New insights into the effect of aging on cardiovascular disease
Aging adults are more likely to have - and die from - cardiovascular disease than their younger counterparts.

Premature death from cardiovascular disease
National data were used to examine changes from 2000 to 2015 in premature death (ages 25 to 64) from cardiovascular disease in the United States.

Ultrasound: The potential power for cardiovascular disease therapy
In the current issue of Cardiovascular Innovations and Applications volume 4, issue 2, pp.

Despite the ACA, millions of Americans with cardiovascular disease still can't get care
Cardiovascular disease (CVD) is the leading cause of death for Americans, yet millions with CVD or cardiovascular risk factors (CVRF) still can't access the care they need, even years after the implementation of the Affordable Care Act (ACA).

Excess weight and body fat cause cardiovascular disease
In the first Mendelian randomization study to look at this, researchers have found evidence that excess weight and body fat cause a range of heart and blood vessel diseases (rather than just being associated with it).

Read More: Cardiovascular Disease News and Cardiovascular Disease Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.