Anna Salleh - ABC Science Online

Muscles play an integral part in regulating cholesterol levels, according to animal studies by Australian researchers - making muscles a prime target for future cholesterol-lowering drugs.

The study of muscle tissue in mice, led by Dr George Muscat of the Institute for Molecular Bioscience at Brisbane's University of Queensland, was published in a recent issue of the Journal of Biological Chemistry.

It was part of research funded by a U.S. biotechnology company, X-Ceptor Therapeutics, which is developing drugs that reduce cholesterol absorption.

"The current scientific wisdom is that cholesterol regulation depends on how much you take in via your diet, how much your body makes itself, and how much is broken down in the liver," he told ABC Science Online. But there was circumstantial evidence that muscle mass was also important, he said.

Previous research had shown that people with a lean body mass who exercised regularly showed increased levels of HDL-cholesterol (high-density lipoprotein). This is often called 'good cholesterol' because it helps remove excess cholesterol from arterial walls and fat deposits, and transports it to the liver, where it is broken down.

"Since muscle accounts for 40 per cent of total body mass and it burns fat and sugar for energy, it is very important to study its role in cholesterol regulation," said Muscat.

Muscle cells contain receptors called LXRs (Liver X Receptors), which are associated with cholesterol clearance in the liver and intestine but, until now, no-one has yet established their functional role in muscle tissue.

Scientists believe that LXRs act like locks which are activated by a cholesterol key called hydroxycholesterol, which in turn triggers genes that code for proteins called ABC Transporters. These in turn help transfer cholesterol to HDL.

Muscat said researchers at X-Ceptor Therapeutics had found that drugs which mimicked the cholesterol 'key' boosted clearance of LDL in rats and reduced atherosclerosis. But they were uncertain whether LXRs in muscle were playing a significant role in this.

In order to find out, Muscat treated two groups of mice with the drug 'key'. One group carried normal LXRs, while the other group did not have LXRs. He then analysed samples of each group's muscle tissue to check for activation of ABC Transporter genes. He found that ABC Transporter genes were turned on in the normal mice, but not in the mice with no LXR receptors.

"This proves that muscle LXRs can be a target for cholesterol lowering medication," he said.

As well as removing cholesterol from tissues, ABC Transporters also remove excess cholesterol that comes into the intestine via the diet, he said. "So a drug based on this could also reduce cholesterol from a high dietary intake as well," Muscat said.

However, the drug does have side effects - it raises the level of triglycerides, which is not desirable. Muscat said researchers at X-Ceptor Therapeutics were now trying to work around this problem.

"There are two forms of LXRs, and one may be useful for activating ABC Transporter genes without raising triglycerides as well," he said.

Muscat now has a grant from Australia's National Health and Medical Research Council to increase general understanding of all the genes activated by LXRs in muscle. As well as evaluating the role of LXR in the body, this information will be useful in drug research, he said.