Science

Neuroendocrine signals control plasma cholesterol levels

Last Updated: 2010-06-10 12:06:19 -0400 (Reuters Health)

By Karla Gale

NEW YORK (Reuters Health) - A gut-brain interaction that regulates aspects of the metabolic syndrome also controls circulating levels of cholesterol, according to research published online June 6th in Nature Neuroscience.

Ultimately, these findings may lead to new targeted drugs that "not only control obesity, diabetes, and hypertension, but also treat lipid abnormalities and 'bad' cholesterol," senior author Dr. Matthias H. Tschop from the University of Cincinnati in Ohio told Reuters Health.

He and his colleagues had wondered why all the other factors of metabolic syndrome would be under control by the brain but not this important step, given that cholesterol is so critical for cardiovascular health and liver metabolism. "So we figured that the brain must have an impact on how much cholesterol is in our bloodstream at a given time," he said.

"It took us 5 years then to tease this apart," he added.

Specifically, they found that a three-pronged "gut-brain axis" involving the central melanocortin system - particularly melanocortin receptor 4 (MC4-R) - as well as ghrelin and glucagon-like peptide 1 (GLP-1) directly regulates cholesterol reuptake by the liver.

By injecting the hunger-inducing hormone ghrelin or a melanocortin receptor antagonist directly into the brain, they could manipulate plasma levels of HDL cholesterol. (Dr. Tschop noted that rodents have very little LDL cholesterol, so HDL cholesterol represents total cholesterol.) Genetically manipulated animals yielded similar results.

Recognizing that this represented a "chicken and egg" event - did the rodents have higher cholesterol levels because they were getting fatter, or vice versa - the researchers restricted calorie intake and found that "cholesterol still went up and down depending on how we affected signaling in the brain," Dr. Tschop said.

Further experiments downregulating gene expression of a major hepatic receptor responsible for HDL-cholesterol re-uptake indicated that this is the major pathway under neuroendocrine control. By contrast, there was much less effect on pathways involved in cholesterol synthesis.

According to Dr. Tschop, their suspicions were confirmed when they infused labeled cholesterol into rats and saw that "disappearance of cholesterol from the blood into the liver differs when you mess with brain signaling."

When they cut the vagus nerve to the liver, manipulating MC4-R no longer altered blood cholesterol levels, so he believes the autonomic nervous system is responsible for this interaction between the brain and the liver.

Eventually, he hopes their research leads to treatment of metabolic syndrome simply by targeting MC4-R. But first, scientists need to see how these findings translate into humans, and how human signaling pathways differentiate LDL from HDL cholesterol.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.2569.html

Nature Neurosci 2010.