Role of ACAT1 in Atherosclerosis and Alzheimer's Disease

Abstract

The acyl‐coenzyme A: cholesterol acyltransferase (ACAT) intracellular membrane protein is located in the endoplasmic reticulum and is composed of 427 amino acids. ACAT is a part of the membrane‐bound O‐acyltransferase enzyme family (MBOAT). MBOATs are recognized by their most carried residues, histamine, and arginine, and are used in lipid synthesis, phospholipid remodeling, and peptide acylation. The enzyme itself is structured as a tetramer split into two homodimers. Nine transmembrane helices or domains (TMs) are on each monomer, the most notable being a cavity formed through TMs 4‐9 harboring histidine, an amino acid tied to catalysis and enzymatic activity.The ACAT1 protein‐coupled with its ACAT2 counterpart catalyze the storage of cholesteryl esters. ACAT2 differs from ACAT1 in function and structure. ACAT2 contains 2 domains and is mainly expressed in intestinal cells and controls lipoprotein particle secretion. The enzyme transfers an acyl group to 3β‐hydroxyl of cholesterol, a cholesterol‐binding site, to form cytosolic lipid droplets that are used for reducing membrane fluidity of the cell. Lipo‐protein‐induced ACAT in microphages is key to the creation of atheroma foam cells, cells characterized by the aggregation of these fatty plaque deposits on the walls of arteries, thus appearing like foam. The aggregation of this plaque to eventually narrow and harden arteries to obstruct blood flow is atherosclerosis. ACAT1 also maintains homeostasis during periods of cholesterol overload in the ER. Other functions of the protein include aiding lipoprotein synthesis and dietary LDL absorption.Recent studies have seen a pathogenic connection between cholesterol and Alzheimer’s disease or other neurodegenerative diseases. Cells contain a membrane that contains microdomains rich in cholesterol. The microdomains assist in the maintenance and growth of the cell and cell membrane; however, it is the disruption of these microdomains through individual disease‐causing toxins that cause them to inactivate ACAT1 and block cholesterol storage, disrupting brain activity.ACAT is currently being studied for its targeted drug therapy countering atherosclerosis. Current studies have proved ACAT inhibition to be ineffective, but there still remains potential immunotherapies to neurodegenerative disorders through the ACAT enzyme. Further research remains to be done to analyze the link between neurodegenerative disorders and the ACAT1 protein.