A protein that regulates cholesterol levels in the body also is responsible for maintaining a healthy balance between fat storage and fat burning, according to a UT Southwestern Medical Center study that may lead to new drug targets in the fight against obesity.
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, a finding that provided more evidence of the role LXR plays in regulating the balance between fat burning and fat storage.
"In the animals lacking LXR, not only can they not store fat, but their cholesterol concentrations build to excessive levels, which somehow drives the animals to burn fat," said Dr. Mangelsdorf, who holds the Doris and Bryan Wildenthal Distinguished Chair in Medical Science. "There is some cholesterol-related signal that the liver sends out that permits fat-burning to happen, and uncovering that signal is the big mystery we're trying to solve next, which may have therapeutic applications."
A better understanding of the cholesterol-driven, fat-burning signal may lead to drugs that control the signal and boost the body's ability to burn unwanted fat instead of storing it, Dr. Mangelsdorf said. The research also may aid in the development of cholesterol-related drugs. High levels of low-density lipoproteins, or "bad" cholesterol, in humans is a major risk factor for heart disease, heart attack and stroke because it contributes to the buildup of plaque that clogs the walls of arteries.
Previous studies have pointed to a protein called SREBP-1c as the primary component in the biochemical pathway that regulates fat metabolism. When an animal eats a meal rich in nutrients, insulin levels in its body go up. Insulin signals to the SREBP-1c protein to activate subsequent components of the pathway, allowing the body to store incoming nutrients as fat.