Scientists at Wake Forest University School of Medicine and colleagues have developed new research mice to help them better understand how the body makes and uses "good" cholesterol to protect against heart attacks and strokes.
"Being able to develop drugs to raise levels of good cholesterol depends on knowing more about the how and where the particles are formed," said John S. Parks, Ph.D., from Wake Forest University School of Medicine. "These animals provide the first tools to address these questions."
High-density lipoprotein (HDL) cholesterol is called "good" cholesterol because higher levels are associated with lower risk of heart attacks. Physicians and scientists believe that HDL carries cholesterol away from the blood vessels and to the liver, where it is passed from the body. It may also help remove excess cholesterol from plaque in arteries, slowing the buildup that can lead to heart attacks and strokes.
Parks, a professor of pathology in the Section on Lipid Sciences, is part of a multi-center team that has developed three groups of research mice to investigate the complexities of good cholesterol. These specially developed mice have mutations in a gene (ABCA1) involved in HDL production. The scientists are using them to pinpoint where good cholesterol is produced and how it helps fight plaque buildup. In one group of animals, the ABCA1 gene is selectively deleted in the liver -- which means their livers cannot produce HDL. It was through studying these mice that the scientists were able to report in 2005 that the liver is likely the body's main source of good cholesterol -- producing 70 to 80 percent.
Now, in the Journal of Clinical Investigation, they report that the intestines are the other source -- producing 20 to 30 percent. This finding came from studying mice with the ABCA1 gene deleted in the intestine. Before these findings, scientists had thought that HDL formation occurred throughout the body -- rather than coming from specific organs.
Scientists also know that very small amounts of HDL are produced in macrophages, cells in the blood vessel walls that are involved in the formation of plaques. Through studying the third group of mice -- which produces no HDL in the vessel walls -- the scientists hope to answer a conundrum about this source of good cholesterol. Previous research indicates that while the levels of HDL produced in the vessels are very small, it may play a large role in keeping the vessels healthy.
Knowing exactly what organs produce good cholesterol -- and which sources are most important in fighting vessel disease -- will allow drug developers to target specific organs to raise HDL levels. Currently, there are few drugs to raise HDL levels, and people who need to raise their HDL levels are advised to get more exercise.
The group will use the mice to evaluate potential drug therapies. Several drugs have been developed that can stimulate the ABCA1 gene to produce good cholesterol, but they aren't useable in humans because of negative side effects. The scientists hope to learn more about how the drugs work and how they could be improved.
"The animals can help us determine which pathways are affected by drug therapy, which can eventually be translated to human studies," said Parks. "They are a valuable tool in the quest to find a therapy to raise HDL concentrations and retard the development of heart disease."
Parks's colleagues on the current research are from the University of British Columbia in Vancouver, Canada, University Medical Center Groningen, The Netherlands, Academic Medical Center, Amsterdam, The Netherlands, State University of New York Downstate Medical Center, and Institut Pasteur de Lille and Faculte de Pharmacie, France.
Their latest findings are reported in the April issue of the Journal of Clinical Investigation.
The research was supported by the National Institutes of Health, Canadian Institutes of Health Research, and the Heart and Stroke Foundation of British Columbia and the Yukon.
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