Atherogenic lipoproteins resulting from genetic defects of apolipoproteins B and E.

Accelerated atherosclerosis occurs in patients with type III hyperlipoproteinemia and familial hypercholesterolemia. These genetic disorders focus attention on specific types of lipoproteins as being responsible for the development of accelerated coronary artery heart disease. The accumulation of chylomicron remnants of intestinal origin and of VLDL remnants or IDL of hepatic origin observed in type III hyperlipoproteinemia appears to correlate with coronary disease. The presence of defective forms of apo E prevents normal receptor-mediated catabolism of these lipoproteins. Patients with familial hypercholesterolemia have an elevation of plasma LDL (and to a lesser extent an increase in VLDL remnants and IDL) secondary to defective LDL receptors that impair normal catabolism. Familial defective apo B100 is secondary to an abnormality of apo B100 that prevents the normal interaction of LDL with the LDL receptor and increases plasma LDL. However, it has not yet been established that familial defective apo B100 predisposes affected individuals to accelerated atherosclerosis. Animals fed diets high in saturated fat and cholesterol have an accumulation of beta-VLDL, IDL, and LDL that resembles the changes in lipoproteins observed in patients with these genetic disorders. Macrophages (which are presumably derived from circulating monocytes) have emerged as a likely key component in atherogenesis because they appear to be progenitors of foam cells in arterial lesions. Macrophages in the arterial wall express receptors that recognize chylomicron remnants and VLDL remnants (beta-VLDL) and chemically modified LDL. Thus, in the presence of these specific lipoproteins, macrophages are converted to cells that resemble foam cells. The precise stimulus that causes monocyte-derived macrophages to enter specific regions of the arterial wall remains to be determined.