UT Southwestern researchers discover role of two genes involved in cholesterol excretion

November 18, 2002

DALLAS - Nov. 18, 2002 - Two specific genes involved in cholesterol transport are required for the most common way excess cholesterol is expelled from our bodies, according to scientists at UT Southwestern Medical Center at Dallas.

The genes, the researchers report, are essential for efficient secretion of cholesterol into the bile, which is the major route that cholesterol exits the body. The discovery sheds new light on potential therapies that could play an important role in reducing high cholesterol, a major risk factor of atherosclerotic diseases, such as coronary heart disease and stroke.

The new findings are reported in this week's issue of the Proceedings of the National Academy of Sciences.

"The disruption of the two genes, Abcg5 and Abcg8, reveals their crucial role in biliary cholesterol secretion," said Dr. Liqing Yu, an instructor in the Eugene McDermott Center for Human Growth and Development and in molecular genetics and lead author of the study. "In humans and mice, the secretion of cholesterol into the bile is essential for maintaining cholesterol homeostasis and constitutes a major defense against the accumulation of dietary cholesterol in blood and tissues."

Dr. Helen Hobbs, senior author of the study, said, "By activating or upregulating Abcg5 and Abcg8 you could theoretically reduce cholesterol in the body by increasing cholesterol transport into the bile and limiting cholesterol absorption. This may also reduce cholesterol in the blood." Hobbs directs the Eugene McDermott Center for Human Growth and Development and the Donald W. Reynolds Cardiovascular Clinical Research Center. She also is an investigator in UT Southwestern's Howard Hughes Medical Institute.

The researchers uncovered this critical pathway by studying mice that lacked the genes.

When researchers fed the mice high cholesterol diets, "We discovered that the fatty liver was developed due to a massive accumulation of cholesterol," Yu said. "We think this happens because the dietary cholesterol cannot be efficiently secreted into the bile, but it is accumulated in the liver and plasma when Abcg5 and Abcg8 are disrupted."

Liver and plasma cholesterol levels were increased by as much as 18-fold and 2.4-fold, respectively, in the mice after they ate a cholesterol-rich diet. Disruption of the two genes also resulted in a 30-fold increase in plasma levels of sitosterol, the major plant sterol, and a two- to threefold increase in fractional absorption of dietary plant sterols.

"Plant sterols are similar to cholesterol, structurally, and in the absence of Abcg5 and Abcg8 the compounds accumulate in the body, which leads to a rare inherited disease called sitosterolemia," Yu said. "Individuals with this disease have dramatically increased plasma plant sterol levels, which is associated with premature atherosclerotic coronary heart disease."

UT Southwestern researchers, in conjunction with researchers at Tularik Inc., discovered the two genes in 2000.

Before scientists identified the genes, the molecular mechanism by which dietary cholesterol is absorbed and the mechanisms by which cholesterol and other sterols are secreted into the bile were not known, Hobbs said.

"The actual discovery of the two genes in 2000 led to a better understanding of two important pathways of cholesterol metabolism," she said.
-end-
Other UT Southwestern researchers involved in the study were Dr. Jonathan Cohen, associate professor of internal medicine; Dr. Robert Hammer, professor of biochemistry; and Dr. Jia Li-Hawkins, now with Pfizer. Researchers from the University of Bonn in Germany also contributed.

The studies were supported by The Howard Hughes Medical Institute, the National Institutes of Health, the Perot Fund; the W. M. Keck Foundation; and the Donald W. Reynolds Cardiovascular Clinical Research Center.

To automatically receive news releases from UT Southwestern via e-mail, go to http://www3.utsouthwestern.edu/ and click on "Latest News." Then go to "Receive our News" to subscribe.

UT Southwestern Medical Center

Related Cholesterol Articles from Brightsurf:

Cholesterol's effects on cellular membranes
The findings have far-reaching implications in the general understanding of disease, the design of drug delivery methods, and many other biological applications that require specific assumptions about the role of cholesterol in cell membranes.

Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.

Microbes might manage your cholesterol
Researchers discover a link between human blood cholesterol levels and a gene in the microbiome that could one day help people manage their cholesterol through diet, probiotics, or entirely new types of treatment.

Experimental cholesterol-lowering drug effective at lowering bad cholesterol, study shows
Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov.

Rethinking how cholesterol is integrated into cells
Cholesterol is best known in connection with cardiovascular disease, but cholesterol is also vital for many fundamental processes in the body.

Seed oils are best for LDL cholesterol
Using a statistical technique called network meta-analysis, researchers have combined the results of dozens of studies of dietary oils to identify those with the best effect on patients' LDL cholesterol and other blood lipids.

Cholesterol leash: Key tethering protein found to transport cellular cholesterol
Cholesterol is an essential component of living organisms, but the mechanisms that transport cholesterol inside the cell are poorly understood.

New way to treat cholesterol may be on the horizon
A breakthrough discovery by scientists at Houston Methodist Research Institute could change the way we treat cholesterol.

How low should LDL cholesterol go?
New analysis shows that in a high-risk population, achieving ultra-low LDL cholesterol levels, down to <10 mg/dL, safely results in additional lowering of risk of cardiovascular events.

Does boosting 'good' cholesterol really improve your health?
A new review addresses the mysteries behind 'good' HDL cholesterol and why boosting its levels does not necessarily provide protection from cardiovascular risk for patients.

Read More: Cholesterol News and Cholesterol 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.