Can cholesterol be made to “behave” in order to prevent heart disease? This is a question examined by Thacker and colleagues in a study recently published in the Journal of Lipid Research. Heart disease is often associated with atherosclerosis, a term used to describe the build-up of plaque on the walls of arteries and other blood vessels, which can cause hardening and narrowing of the arteries. The build-up of plaque may lead to the arteries becoming blocked and restrict blood flow to various areas of your body. Overtime atherosclerosis can lead to heart attack, stroke or even death.
The plaque that forms on blood vessels is made up of cholesterol, fat and other substances found in the blood. For most people, hearing the word cholesterol invokes something that is bad. However, cholesterol is very important for the functioning of cells and tissues in the human body. There is a fine balance of having just enough and having too much cholesterol. High levels of cholesterol in the blood are a major cause of atherosclerosis. There are multiple components of our blood that help regulate the levels of cholesterol including high-density lipoprotein (HDL) and low-density lipoprotein (LDL). HDL, also known as good cholesterol, picks up excess cholesterol from the blood and takes it to the liver to be broken down. LDL, also known as bad cholesterol, picks up excess cholesterol and deposits it onto your artery walls, eventually forming a plaque. Thus, the “winner” of the tug-of-war between HDL and LDL determines how cholesterol impacts health.
What can tip this tug of war in favour of HDL to benefit human health? One possibility is the protein LCAT, found in the bloodstream. LCAT processes excess cholesterol through a chemical modification called esterification. The chemical processing of cholesterol by LCAT changes how it is distributed in the body. One way to think of this system is to compare it to the mail system. LCAT is the worker at the post office who is responsible for sorting mail and HDL and LDL are the mailmen who deliver the mail to the correct destination. LCAT’s job is to ensure cholesterol is picked up by the mailmen and is sent off to its destination.
Researchers at the National Heart, Lung and Blood Institute in Bethesda, Maryland wanted to investigate the impact of LCAT on processing excess cholesterol. The researchers used mice to explore LCAT’s function and examined the levels of cholesterol and other fats in the blood and examined plaque formation in the heart. When cholesterol is processed by LCAT, the researchers found HDL would preferentially pick up cholesterol from the blood and transport it to the liver for break-down. In effect, LCAT processes cholesterol by putting a sticker on it; this sticker tells the HDL “mailman” to pick it up and deliver it to the liver, which gets rid of this excess cholesterol. These researchers also found that other blood components such as red blood cells (RBC) and immune cells are better at getting rid of cholesterol when LCAT is present.
Overall this study found that LCAT increases the ability of cells to get rid of excess cholesterol, by increasing transport of cholesterol to the liver, such that less cholesterol is available to form plaques that lead to heart disease. LCAT is a “good cop”, tipping the balance of cholesterol back to normal when levels are elevated. This research provides some possible future directions in which LCAT could be a therapeutic target for treating atherosclerosis. This would improve the lives of those who suffer from heart disease.
Thacker SG, Rousset X, Esmail SY, Zarzour A, Jin X, Collins HL, Sampson M, Stonik J, Demosky S, Malide DA, Freeman L, Vaisman BL, Kruth HS, Adelman SJ, and Remaley AT (2015). Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice. Journal of Lipid Research, 56(7): 1282-95. doi: 10.1194/jlr.M048629.