The role of cholesterol efflux in macrophage cholesterol homeostasis

Abstract

The development of atherosclerosis can be influenced by genetic or pharmacologic disruptions of cellular cholesterol homeostasis. Cholesterol homeostasis in macrophages is of critical importance because these cells have a pivotal function in the vessel wall and in the development of atherosclerotic lesions. Macrophages scavenge modified lipoproteins in the walls of blood vessels and transform into foam cells as cholesterol accumulates intracellularly. Research on apolipoprotein (apo) E, apoAI, and the ATP-Binding Cassette (ABC) A1 transporter suggests that cholesterol efflux has a role in macrophage cholesterol homeostasis that directly affects atherosclerosis risk. Few studies have been done to characterize the interactions between efflux and the other processes of cholesterol balance in the macrophages of atherosclerosis models. The objective of this thesis was to identify the connections between cholesterol efflux and cellular cholesterol homeostasis in macrophages with genotypes that are known to affect the progression of atherosclerosis. To fulfill this objective, we measured the efflux, storage, uptake, and synthesis of cholesterol in peritoneal macrophages from different genetically engineered mice. Our results show that cholesterol storage deficits resulting from the genetic deletion of the cholesterol esterifying enzyme, acyl-coenzyme A: cholesterol acyltransferase (ACAT), disrupted cholesterol efflux, increased lipoprotein uptake, increased cholesterol synthesis, and altered cellular morphology. Our studies also show that macrophages that endogenously synthesize apoE or transgenic apoAI have increased cholesterol efflux due to the concentration of these cholesterol acceptors in the extracellular space and to the stimulation of cholesterol efflux pathways. The current in vitro studies support the idea that cholesterol efflux helps to maintain cholesterol homeostasis in macrophages. Together, these studies suggest that cholesterol efflux is a mechanism that protects against foam cell formation and atherosclerosis.