The research, published in today’s issue of Science and done in collaboration with Baylor College of Medicine in Houston, shows that guggulsterone blocks the FXR receptor, which regulates cholesterol metabolism.
Dr. David Mangelsdorf, professor of pharmacology and an investigator in the Howard Hughes Medical Institute (HHMI) at UT Southwestern, and his colleagues previously had revealed FXR’s role in the body’s conversion of cholesterol to bile acids. When the bile acids reach a certain level in the body, FXR is activated to interrupt the cholesterol-to-bile-acid process.
“The receptor keeps bile acids in check,” Mangelsdorf said. “If you disturb it, it changes how cholesterol is metabolized.”
Researchers at Baylor discovered that guggulsterone – made from the sap of Commiphora mukul, a tree commonly known in India as guggul – blocked FXR activity in a gene assay. Assays are flat panels used to study genetic activity outside living bodies. Mangelsdorf and his colleagues had used mouse models created for their earlier FXR studies. Those FXR-positive and FXR-negative mouse models allowed the researchers to test whether guggulsterone and FXR reacted the same way in living bodies as they did in the assays.
The mouse model tests confirmed the assay results and showed that cholesterol levels fell in FXR-positive mice that were given guggulsterone.
Mangelsdorf believes the work could lead to new drugs to control cholesterol by creating compounds based on the chemical structure of guggulsterone. Those drugs would prevent FXR from interrupting cholesterol metabolism in people whose bodies aren’t getting rid of enough cholesterol before the process shuts down.
The gum resin of the guggul tree has been used in Ayurvedic medicine, a traditional Hindu medicine practiced in India for nearly 3,000 years, to treat a wide variety of ailments, including obesity and lipid disorders. An ethyl acetate extract of this resin has been found to lower low-density lipoprotein cholesterol and triglycerides in humans. Since receiving regulatory approval in India in 1987, this extract, called guglipid, has been widely and effectively used to treat hyperlipidemia, according to the study researchers.
Amy Liverman, a student research assistant in Mangelsdorf’s lab, led UT Southwestern’s contributions to the research. X-Ceptor Therapeutics Inc. of San Diego also contributed to the research.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the U.S. Department of Agriculture, the National Institute of General Medical Sciences, HHMI, and the Robert A. Welch Foundation.
Journal
Science