Although cholesterol has often been linked with heart disease and an unhealthy lifestyle, its properties as a lipid make it essential for the health of membranes that surround individual cells.
Cholesterol is found in every cell of the body and helps to digest fats, strengthen cell membranes and make hormones. Although cholesterol has many important functions, excess cholesterol can build up on artery walls and cause atherosclerosis leading to heart attack and stroke. Therefore, a great deal of research has gone into finding ways of lowering the body's cholesterol levels.
There is a thriving market for cholesterol-lowering drugs with Schering-Plough and Merck's Zetia (ezetimibe) as one of the newer entrants in an estimated $20 billion (€15.1 billion)-a-year statin market.
The research, performed by scientists at the UT Southwestern Medical Centre, focused on regions of the membrane where cholesterol is enriched. These regions, called lipid domains, are more rigid than the rest of the cell membrane because of cholesterol and play a critical role in organising signalling machinery at the cell surface. The correct arrangement of signalling modules in these domains is vital for communication inside the cell and is dependent on proper levels of cholesterol.
While studying how cholesterol moves to the membrane to get to lipid domains, lead researcher, Dr Richard Anderson, and colleagues found that cholesterol could work outside the membrane to regulate a key-signalling pathway that occurs inside the cell.
Through an interaction with a protein called the oxysterol binding protein (OSBP), cholesterol holds together a group of enzymes that deactivates extracellular signal-related kinase (ERK). Overactive ERK is associated with multiple cancers.
When the amount of cholesterol in lipid domains is normal, the OSBP-cholesterol complex keeps the amount of active ERK under control. When cholesterol in the domains gets too low, the complex falls apart, leading to abnormally high levels of active ERK.
Researchers revealed that OSBP has binding sites for both cholesterol and the other proteins in the complex. When cholesterol binds OSBP it changes shape to bind the key enzymes in a way that allows them to work together to control deactivation of ERK. When lipid domain cholesterol gets low, OSBP loses its cholesterol and no longer is able to bind the enzymes that deactivate ERK, keeping it active.
"OSBP appears to work like a cholesterol-regulated scaffolding protein that controls a key signalling pathway," Dr Anderson said "This work shows a new way that lipids can regulate key signalling pathways and raises the possibility that other lipid regulated signalling scaffolds can malfunction in other diseases."