Researchers at UT Southwestern have identified the defective genes responsible for a rare genetic disorder--a discover that sheds light on the process by which the body regulatescholesterol and other sterols from the diet. It also provides new insights into the way the body acquires and gets rid of cholesterol and other sterols. The disorder, sitosterolemia, is characterized by hyperabsorption of cholesterol and plant sterols. This leads to an excessive presence of cholesterol in the blood, which ultimately causes premature heart disease.
"The main benefit of this study is that we identified a key protein in two very poorly understood pathways--the mechanisms by which cholesterol and other sterols are secreted into the bile," said Dr. Helen Hobbs, professor of internal medicine and molecular genetics and senior author of the study.
"Now we have a handle on one of the key players in cholesterol absorption." she said. Until this discovery, which was published in Science, the key proteins involved in the regulation of cholesterol absorption and its secretion into the bile were not known, said Dr. Hobbs, director of the Eugene McDermott Center for Human Growth and Development.
In healthy people, cholesterol is absorbed by the intestine and quickly excreted into the bile. Of the average 250 milligrams to 350 milligrams of cholesterol consumed by healthy individuals daily, only 35 to 45 % is actually absorbed. People with sitosterolemia absorb 50 percent to 60 percent of ingested cholesterol. "The body usually absorbs very small amounts of plant sterols, such as sitosterol, from the diet," said Dr. Hobbs, holder of the Dallas Heart Ball Chair in Cardiology Research and the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development. "Those plant sterols that reach the liver are preferentially excreted into the bile.
"In people with sitosterolemia, these sterols, like cholesterol, are absorbed at an increased rate and excreted into the bile at a reduced rate. As a consequence, patients with sitosterolemia have high concentrations of sitosterol and other plant sterols in the blood."
"Other UT Southwestern researchers participating in the study included Drs. Knut Berge and Gregory Graf, postdoctoral research fellows in molecular genetics; Dr. Liqing Yu, assistant instructor in molecular genetics; and Robert Barnes, a programmer analyst in the Eugene McDermott Center for Human Growth and Development. This work was performed in collaboration with Drs. Bei Shan and Hui Tian of the pharmaceutical company, Tularik Inch. The study was supported by grants from the National Institutes of Health, the W.M. Keck Foundation, the Donald W. Reynolds Cardiovascular Clinical Research Center and the Norwegian Research Council.
