Macrophage Reverse Cholesterol Transport

Abstract

The concept of “reverse cholesterol transport” (RCT) was first introduced in 1968 by Glomset1 to describe the process by which extrahepatic (peripheral) cholesterol is returned to the liver for excretion in the bile and ultimately the feces. The physiological need for this process is clear, as nonhepatic cells acquire cholesterol through uptake of lipoproteins and de novo synthesis and yet (with the exception of steroidogenic tissues that convert cholesterol to steroid hormones) are unable to catabolize it. Excess unesterified cholesterol (UC) is toxic to cells, and therefore, cells have developed several ways to protect themselves against cholesterol toxicity. One key pathway is the efflux of cholesterol to extracellular “acceptors.” The return of this “peripheral” cholesterol to the liver is necessary to balance cholesterol intake and de novo synthesis and thus to maintain whole-body steady-state cholesterol metabolism.The relationship of RCT to atherosclerosis was first suggested by Ross and Glomset,2 who hypothesized that atherosclerotic lesions develop when an imbalance occurs between the deposition and removal of arterial cholesterol after endothelial injury. This concept was further developed by Miller and Miller,3 who suggested that on the basis of the inverse relation between HDL cholesterol (HDL-C) and cardiovascular disease, emphasis should be placed on increasing HDL as a way to increase clearance of cholesterol from the arterial wall to prevent cardiovascular disease. Despite 3 decades of work, the relationship of RCT to atherosclerosis remains more of a hypothesis than an established fact. Because the physiological process of RCT clearly occurs from all peripheral tissues, it has often been measured and discussed as a general peripheral process. However, in atherosclerotic lesions, the primary cell type that is overloaded with cholesterol is the macrophage, and therefore, it makes more sense to conceptualize and measure RCT as a macrophage-specific phenomenon when it comes …