The liver may produce most of the body's good cholesterol

Research in mice suggests that the liver may produce most of the body's "good" cholesterol, an unexpected finding that might one day help scientists develop new treatments to raise levels of this heart-protecting molecule in humans.

In the May issue of the Journal of Clinical Investigation, researchers from Wake Forest University School of Medicine and colleagues will report on a project that used gene-targeting in mice to simulate a rare disease in people – Tangier disease. People with this genetic disease produce virtually no "good" cholesterol.

"In studies of mice, we provided the first definitive proof that the liver is the source of about 80 percent of the high-density lipoprotein (HDL), or 'good' cholesterol, that circulates in the blood," said John S. Parks, Ph.D., senior researcher, from the school of medicine, which is part of Wake Forest University Baptist Medical Center. "Understanding more about how HDL is produced could lead to new treatments to raise its levels."

Learning more about Tangier disease could help people with less severe cholesterol disorders, Parks said. Low levels of HDL are associated with higher risk of heart attacks, even when total cholesterol levels are normal.

People with Tangier disease have mutations in a gene (ABCA1) involved in the production of HDL. Like all genes, ABCA1 exerts its effects through a protein that it manufactures. The ABCA1 protein is found in many parts of the body, so scientists have been unsure which specific tissues are involved in HDL production. They suspected the liver played an important role because of high levels of ABCA1 there.

To test their hypothesis and learn more about how HDL is produced, the researchers developed mice without the ABCA1 gene in the liver – which means their livers cannot produce HDL. The researchers measured HDL levels in these mice and found that concentrations of HDL were 80 percent lower than in normal mice. The mice also had higher levels of triglycerides, as do patients with Tangier disease.

Until now, scientists had thought that HDL formation occurred throughout the body – rather than coming mainly from one organ. They know that some of it is manufactured in the walls of blood vessels, for example.

"These results profoundly alter our concept of how HDL is manufactured in the body and establish the liver as the single most important source of HDL in a mouse model," said Parks, a professor of pathology.

Parks said the finding could be important in drug development. "If we want to raise HDL levels, it might make sense to focus on drugs that target the liver," he said.

Parks said research into Tangier disease is a good example of how learning more about a rare disease can lead to important new information.

"When studying the basic mechanisms of a rare disorder you often learn lessons from nature that have other applications," he said.

For example, scientists have learned that the ABCA1 gene may play a role in Alzheimer's disease and prostate cancer. Parks and colleagues hope to collaborate with other scientists to learn more about the role of ABCA1 in these diseases.

They are also starting a project to compare the effects of the HDL produced in the liver with the HDL produced in the walls of blood vessels.

"We will look at levels of heart disease in mice that cannot produce HDL in the liver versus mice that cannot produce it in the vessel walls," said Parks.

Parks' colleagues on the current research are from the University of North Carolina at Chapel Hill, the University of British Columbia in Vancouver, Canada, and the University of Maryland School of Medicine.

The research was supported by the National Institutes of Health, Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, The Saal van Zwangenberg foundation, the Netherlands Heart Foundation and the Heart and Stroke Foundation of British Columbia and the Yukon.

Tangier disease is named for an island off the coast of Virginia where the disease was first discovered. The disease is extremely rare. As of 1992, fewer than 50 cases had been identified worldwide.