Protein that regulates cholesterol levels may lead to new drug targets in the fight against obesity

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.

But Dr. Mangelsdorf's research group has shown that LXRs actually regulate SREBP-1c, activating the gene responsible for making the SREBP-1c protein in the first place.

"LXR, this cholesterol sensor, is required for SREBP-1c to be expressed, to get SREBP-1c to initiate its role in regulating fat storage," said Dr. Mangelsdorf, who discovered the LXR protein and the gene responsible for making it. "SREBP-1c had been considered the master regulator of fat synthesis, but our studies have shown that LXR is the master regulator of the master regulator."

From the point of view of evolution, an animal capable of linking its ability to sense cholesterol with its ability to store fat may have had a survival advantage. An adult mammal has virtually no need for dietary cholesterol because its body can synthesize enough on its own. But LXRs give an animal the ability to sense the cholesterol component of a high-fat diet and get rid of it, while retaining the fat and storing it for times of deprivation.

"Our work suggests that fat storage is inextricably linked to the body's ability to metabolize cholesterol and that the LXRs have evolved as the sensors that govern the unique cross talk between these two important metabolic pathways," Dr. Mangelsdorf said.

Other UT Southwestern researchers involved in the study were Dr. Nada Kalaany, postdoctoral researcher in pharmacology; Dr. Karine Gauthier former postdoctoral fellow; Dr. Pradeep Mammen, assistant professor of internal medicine; Dr. Tatsuya Kitazume, biochemistry postdoctoral researcher; Dr. Julian Peterson, professor of biochemistry; Dr. Jay Horton, associate professor of internal medicine and molecular genetics; and Dr. Daniel Garry, associate professor of internal medicine and molecular biology. Researchers at Harvard Medical School also participated.

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