Natural compound used in India reduces cholesterol by blocking metabolism-controlling receptor

DALLAS – UT Southwestern Medical Center at Dallas researchers have helped prove that a naturally occurring compound used for centuries as a dietary supplement in India can help lower cholesterol levels. The research, published in today’s issue of Science and done in collaboration with Baylor College of Medicine in Houston, shows that guglipid 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 guglipid – made from the sap of Bdellium, a tree commonly known in India – 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 guglipid 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 guglipid.

Mangelsdorf believes the work could lead to new drugs to control cholesterol by creating compounds based on the chemical structure of guglipid. 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 Bdellium 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.

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. The University of Texas Southwestern Medical Center at Dallas Page maintained by: Office of News and Publications.

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Researchers, led by David Moore at the Baylor College of Medicine in Houston, discovered that guglipid acts as an antagonist, binding to and inhibiting the farnesoid X receptor (FXR), a protein that binds to bile acids and halts their production. Moore hypothesized that the binding property of guglipid would inhibit FXR, thereby lowering cholesterol.

To test this theory in vivo, Moore passed his work on to David J. Mangelsdorf, Ph.D., and his colleagues at the University of Texas Southwestern Medical Center, whose research is funded by the Howard Hughes Medical Institute, a nonprofit research institute based in Chevy Chase, Md., that funds scientists throughout universities in the United States. They administered guglipid to two types of mice--wild-type mice with normal FXR function and FXR-knockout mice with no FXR protein--to determine whether FXR was involved in the cholesterol-lowering effect of guglipid.

"When you give guglipid to the wild-type animal, it should lower its cholesterol. If this compound is working through FXR, when you give it to the FXR-knockout, it should have no effect," Mangelsdorf said. "And that was exactly what we saw. We demonstrated definitively in our laboratory that FXR was involved in the process, which is a key point to the paper, because it showed, in vivo, that the mechanism of action was as Dr. Moore's laboratory had suggested." In addition, researchers found that the compound lowered triglyceride levels, although this occurrence was unexplained.

"guglipid is basically an antagonist--it interrupts what a normal protein in the body is doing by blocking its normal action," Mangelsdorf said. "Normally, that action would be good, but blocking [FXR] in this way with people who are hypercholesterolimic or hyperlipidemic may be beneficial because it lowers triglycerides and cholesterol."