San Diego State University researchers have discovered that blocking the activity of two genes that control the production of lipoproteins reduces blood levels of "bad cholesterol" without causing fat retention in the liver.

This discovery provides new opportunities to develop drugs shown to be effective in reducing bad cholesterol and heart disease, but without the unacceptable side effect of fatty deposits on the liver. The discovery is published in the Oct. 6 issue of the Journal of Biological Chemistry.

Funded by the National Institutes of Health, SDSU Heart Institute researchers Roger Davis, Nathan Spann and other team members found that by inhibiting two proteins, microsomal triglyceride transfer protein (MTP) and liver fatty acid-binding protein (L-FABP), liver production of lipoproteins, or the protein-coated packages that carry fat and cholesterol through the bloodstream, can be blocked without causing triglycerides to build on the liver. Normally, these two complementary proteins work together to produce fat and package it into lipoproteins.

Prior to this discovery, pharmaceutical company researchers proved that MTP controlled liver production of lipoproteins. In the 1990s, several drug companies developed MTP inhibitors which were effective in reducing blood levels of bad cholesterol in animals and in humans. Initially, the discovery of MTP inhibitors was seen as a "magic bullet" to reduce heart disease characterized by hardening of the arteries. However, it was discovered that MTP inhibitors also caused fatty liver and could not be used safely in humans and their further development was discontinued.

"This discovery will resurrect the drug development of MTP inhibitors, so they can be used safely and effectively to lower cholesterol in combination with L-FABP inhibitors," Davis, who has been working toward this discovery for 30 years, said. "Additionally, MTP inhibitors appear to be more effective and more easily tolerated than statins."

Statins are the most commonly used drugs for reducing bad cholesterol in blood. They work by removing bad cholesterol from the blood, whereas MTP inhibitors work by blocking its production by the liver. There are some individuals who cannot tolerate statins or do not respond to treatment.

Currently, Davis and Spann, a recent graduate of the SDSU/University of California, San Diego joint doctoral program in cell and molecular biology, are conducting experiments on developing dual MTP/L-FABP inhibitors.

Additionally, San Diego State University Research Foundation has already filed a patent for their discovery.

"Being a part of a discovery that someday might help human disease is one of the most rewarding aspects of completing my Ph.D. thesis," said Spann.

Davis is the first researcher to move into the SDSU BioScience Center, where the connections between inflammation, infection and heart disease are studied. With more than 33,000 square feet of usable space, the center will feature three floors of research laboratories, offices and the 100-seat Alan and Debbie Gold Auditorium for the Life Sciences. The BioScience Center opened in March 2006.

Heart disease and heart attacks remain one of the United States' leading health problems. The American Heart Association estimates more than 1.2 million Americans will have their first or a recurrent heart attack this year. Approximately 479,000 of them will die. In 2006, the Centers for Disease Control project that heart disease will cost the U.S. economy an estimated $142.5 billion, including costs incurred due to health care services, medications and loss of productivity.

The SDSU Heart Institute is sponsored by SDSU's College of Sciences and College of Health and Human Services and includes approximately 30 faculty members from a number of health-related disciplines. Its mission is to promote research and teaching programs relating to heart and cardiovascular system performance in health and disease, and to increase awareness of cardiovascular disease and its prevention in the greater San Diego area.

San Diego State University is the oldest and largest higher education institution in the San Diego region. Since it was founded in 1897, the university has grown to offer bachelor's degrees in 81 areas, master's degrees in 72 areas and doctorates in 16 areas. SDSU's nearly 34,000 students participate in an academic curriculum distinguished by direct contact with faculty and an increasing international emphasis that prepares them for a global future. For more information, visit sdsu.edu.

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