In animals and humans, a protein called the liver X receptor, or LXR, senses cholesterol levels. When these receptors detect rising amounts of cholesterol, they activate genes and a series of biochemical reactions that remove diet-derived cholesterol from the body.
The cholesterol-regulating role of LXRs is well understood, but until now, their role in regulating fat levels was unclear.
In their recent study, UT Southwestern researchers found that "knockout" mice genetically engineered to lack the gene for LXR could not store fat and did not become obese when they were fed a Western-style diet high in both fat and cholesterol. However, knockout mice fed only fat were able to store fat.
High-fat diets typically contain both fat and cholesterol, but this study shows that it is the cholesterol component of a high-fat diet that actually triggers the normal fat-storage process in the body, said Dr. David Mangelsdorf, professor of pharmacology and biochemistry at UT Southwestern and senior author of the study.
"Our studies suggest a dual role for LXRs," said Dr. Mangelsdorf, an investigator in the Howard Hughes Medical Institute at UT Southwestern. "Not only do these receptors sense and limit the accumulation of dietary cholesterol, but their activation by cholesterol is required to initiate a major fat-storing process."
The research appears in the April issue of the journal Cell Metabolism.
Because the knockout mice cannot remove excess dietary cholesterol, the animals develop extremely high cholesterol levels.
Surprisingly, the researchers found that the buildup of cholesterol in the knockout mice actually activates a fat-burning process,
Contact: Amanda Siegfried
UT Southwestern Medical Center