Cholesterol is a waxy lipid molecule necessary for cell membrane integrity and the production of hormones like estrogen and testosterone. While the body requires a steady supply, excessive free cholesterol within cells can become toxic and disrupt normal cellular function. To manage this balance, cells rely on the enzyme Acyl-CoA:cholesterol acyltransferase, or ACAT. ACAT regulates cholesterol storage by converting excess free cholesterol into a safe, inert form, ensuring it can be held in reserve or prepared for transport out of the cell.
The Enzyme’s Core Function in Cholesterol Esterification
ACAT performs esterification, the cell’s primary mechanism for handling an overload of free cholesterol. The enzyme is located within the endoplasmic reticulum, a network of membranes inside the cell where lipid synthesis and processing occur. ACAT catalyzes the joining of a free cholesterol molecule and a fatty acid group donated by Acyl-Coenzyme A (Acyl-CoA). This reaction produces Coenzyme A (CoA) and a cholesterol ester.
The cholesterol ester differs from free cholesterol because the polar hydroxyl group has been blocked by the fatty acid, making the resulting molecule highly hydrophobic. Because of its water-repelling nature, the cholesterol ester cannot integrate into cell membranes. Instead, the newly formed cholesterol esters aggregate into specialized compartments known as cytoplasmic lipid droplets. These lipid droplets prevent the buildup of free cholesterol within the cell’s functional membranes.
Distinct Roles of ACAT1 and ACAT2 in Systemic Management
The body manages cholesterol systemically using two distinct forms of ACAT: ACAT1 and ACAT2. ACAT1 is found in virtually all cell types throughout the body. Its function is to serve as an internal housekeeper, protecting individual cells from toxic accumulation of free cholesterol. ACAT1 activity ensures that cells, such as those in the brain, adrenal glands, and kidneys, can temporarily store cholesterol in lipid droplets for later use or export.
ACAT2 has a restricted tissue distribution, found predominantly in the liver and the cells lining the small intestine, called enterocytes. The function of ACAT2 is tied to the body’s cholesterol transport and absorption mechanisms. In the intestine, ACAT2 esterifies dietary cholesterol absorbed from food, preparing it for packaging into large lipoprotein particles called chylomicrons for transport into the bloodstream. In the liver, ACAT2 contributes to the esterification of cholesterol destined for secretion into the circulation, packaged into very-low-density lipoproteins (VLDL) for delivery to other tissues.
How ACAT Activity Contributes to Atherosclerosis
While ACAT is essential for cellular health, ACAT1 activity becomes a factor in the development of atherosclerosis, or the hardening of the arteries. This process begins when macrophages attempt to clear excess cholesterol, particularly the modified form found in oxidized low-density lipoprotein (LDL), from the arterial wall. These immune cells take up large amounts of cholesterol, leading to a massive influx of free cholesterol inside the cell. To cope with this overwhelming load, the macrophage rapidly activates ACAT1 to esterify the excess free cholesterol for storage.
The intake of cholesterol exceeds the cell’s capacity to export it, causing cholesterol esters to accumulate dramatically in the cytoplasm. This engorgement transforms the macrophage into a characteristic “foam cell,” a defining feature of atherosclerotic lesions. The accumulation of these foam cells beneath the arterial lining initiates the formation of a fatty streak, which matures into a hardened, fibrous plaque. This plaque narrows the artery and can rupture, leading to dangerous blood clots.
This dual nature of ACAT1 made it a target for drug development. Scientists investigated ACAT inhibitors to block foam cell formation and slow the progression of heart disease. The goal was to prevent the storage of cholesterol inside the macrophage, forcing the free cholesterol to be exported or leading to cell death. However, clinical trials showed mixed results due to complexities involving the distinct roles of ACAT1 and ACAT2, and potential toxicity when inhibiting ACAT1’s protective role in other cells.