Acyl-coenzyme A:cholesterol acyltransferase 1, commonly known as ACAT1, is an enzyme present in nearly all human cells. It helps the body process and manage cholesterol within cells by converting it into a storable form, preventing harmful accumulation. Understanding ACAT1’s functions provides insights into various aspects of human health, particularly lipid metabolism.
ACAT1’s Function in Cholesterol Management
ACAT1 serves as a regulator of cholesterol within cells, operating primarily within the endoplasmic reticulum (ER) membrane. Its function involves converting free cholesterol into cholesterol esters (CEs). This conversion occurs by transferring a fatty acyl group from acyl-CoA to cholesterol, creating a storable form of cholesterol.
Cells require this storage mechanism to prevent the buildup of free cholesterol, which can disrupt cell membranes and cellular processes. Stored cholesterol esters are held in cytoplasmic lipid droplets, acting as a reservoir. This stored cholesterol can be retrieved and converted back to free cholesterol when needed for various cellular functions, such as membrane synthesis or the production of steroid hormones.
ACAT1 and Cardiovascular Health
ACAT1’s activity is linked to cardiovascular health, particularly in the context of atherosclerosis, a condition characterized by plaque buildup in arteries. In the early stages of atherosclerosis, macrophages, a type of immune cell, infiltrate arterial walls and take up excessive oxidized low-density lipoprotein (LDL) cholesterol. This excessive uptake leads to the transformation of macrophages into “foam cells,” which are laden with cholesterol esters.
ACAT1 is expressed in these macrophages and contributes to the esterification and accumulation of cholesterol within these foam cells. Accumulation of cholesterol esters within foam cells contributes to the progression of atherosclerotic plaques, narrowing arteries and impeding blood flow. While ACAT1 inhibition was initially thought to reduce cholesterol accumulation in atherosclerotic lesions, some studies have shown that pharmacological inhibition of ACAT1 in macrophages can increase foam cell formation in certain animal models.
ACAT1 in Brain Health
Cholesterol metabolism in the brain is unique from the rest of the body, as the brain largely synthesizes its own cholesterol and has limited exchange with peripheral cholesterol. ACAT1 is the primary ACAT isoform found in brain cells and plays a role in regulating brain cholesterol homeostasis. Its activity in the brain has garnered attention due to its potential connection to neurodegenerative conditions, especially Alzheimer’s disease (AD).
In Alzheimer’s disease, there is an increase in cholesterol ester content in vulnerable regions of the brain. Elevated cholesterol esters are linked with tau pathology in AD patient-derived neurons. Studies in mouse models of Alzheimer’s disease show that reducing ACAT1 activity, either through genetic deletion or pharmacological inhibition, can lead to beneficial effects, including a reduction in amyloid-beta levels and improved cognitive function. This suggests that modulating ACAT1 activity could influence the processing of amyloid-beta, a protein that forms plaques characteristic of Alzheimer’s disease.