Dispelling the notion that circulating levels of good and bad cholesterol in the blood are just the balance of dietary absorption and liver secretion and metabolism, US scientists who did tests on mice suggest that a neural circuit in the brain involving the hunger-signaling hormone ghrelin directly controls cholesterol metabolism by the liver.

You can read about the discovery, led by Dr Matthias Tschöp, professor in the endocrinology division of the University of Cincinnati (UC), Ohio, in the 6 June online ahead of print issue of Nature Neuroscience.

In a statement, Tschöp told the media that:

“We have long thought that cholesterol is exclusively regulated through dietary absorption or synthesis and secretion by the liver.”

“Our study shows for the first time that cholesterol is also under direct ‘remote control’ by specific neurocircuitry in the central nervous system,” he added.

Tschöp and colleagues hope their finding will provide a target for new treatments for controlling cholesterol levels.

Cholesterol, which circulates in the blood along with triglycerides and other lipids, is an essential structural component in cells in mammals and it also helps production of important substances like vitamins, digestive acids and hormones. However, too much cholesterol can result in atherosclerosis, a buildup of plaque in the arteries.

There are two types of cholesterol, the so-called “bad” or low-density lipoprotein (LDL) type, which is thought to be involved in plaque buildup and thus raises risk of metabolic and cardiovascular disorders, and the so-called “good” or high-density lipoprotein (HDL) type, which is thought to be beneficial.

Ghrelin is a hunger-signaling hormone that inhibits the melanocortin 4 receptor (MC4R) in the hypothalamus and plays a key role in regulating food intake and energy use.

Using lab mice, Tschöp and colleagues found that higher levels of ghrelin caused them to develop higher levels of blood-circulating cholesterol, which they attribute to a reduction in uptake by the liver.

When the researchers tested the effect of deleting or blocking MC4R in the central nervous system with chemicals, they found this also led to higher levels of circulating HDL cholesterol, and suggested MC4R was the key part of the “remote control” circuit.

“Inhibiting the brain’s melanocortin system by pharmacological, genetic or endocrine mechanisms increased circulating HDL cholesterol by reducing its uptake by the liver independent of food intake or body weight,” they wrote, concluding that:

“Our data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver.”

Tschöp said they were also “stunned to see that by switching MC4R off in the brain, we could even make injected cholesterol remain in the blood much longer”.

There are differences in the composition of mouse and human cholesterol, so more research is needed to verify if this effect also occurs in humans, cautioned the researchers, but they said nevertheless, these findings add to a growing pile of evidence that the central nervous system is far more involved in the control of essential metabolic processes than we once thought.

The National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases funded the study.

“Melanocortin signaling in the CNS directly regulates circulating cholesterol free.”
Diego Perez-Tilve, Susanna M Hofmann, Joshua Basford, Ruben Nogueiras, Paul T Pfluger, James T Patterson, Erin Grant, Hilary E Wilson-Perez, Norman A Granholm, Myrtha Arnold, James L Trevaskis, Andrew A Butler, William S Davidson, Stephen C Woods, Stephen C Benoit, Mark W Sleeman, Richard D DiMarchi, David Y Hui and Matthias H Tschöp.
Nature Neuroscience Published online 6 June 2010.

Source: University of Cincinnati.

Written by: Catharine Paddock, PhD