Consequences of cellular cholesterol accumulation: basic concepts and physiological implications.

The cells of most organs and tissues satisfy their requirements for membrane cholesterol via endogenous cholesterol biosynthesis (1). Many cell types, however, have acquired mechanisms to internalize exogenous sources of cholesterol, usually in the form of plasma-derived lipoproteins (2). Examples include steroid-synthesizing cells, hepatocytes, and macrophages and smooth muscle cells in atherosclerotic lesions, often referred to as foam cells. In the case of steroidogenic cells, the internalization of lipoprotein-cholesterol represents a physiological process that provides cells with precursor cholesterol stores, to be used for “acute” steroid hormone production (3). Hepatocyte lipoprotein uptake mediates the clearance of various classes of plasma lipoproteins (1), which can lead to whole-body elimination of excess diet-derived cholesterol in the bile, a process known as reverse cholesterol transport (Tall, this Perspective series, ref. 4). The uptake of arterial-wall lipoproteins by macrophages and smooth muscle cells may be a type of physiological scavenging response that initially helps rid the endothelium of potentially harmful lipoprotein material (5). As will be discussed below, however, this cellular process eventually contributes to the progression and complications of atherosclerotic vascular disease.