Abnormalities in metabolism of low density lipoproteins associated with coronary heart disease.

Low density lipoprotein (LDL) is probably the most atherogenic of all the lipoproteins. Several abnormalities in LDL metabolism seem to be associated with coronary heart disease (CHD) one of them being an elevation of plasma LDL concentration. Recent findings suggest that disorders in the metabolism of LDL could be associated with accelerated atherosclerosis even without elevated LDL levels such as increased flux of LDL and changes in the LDL composition. Elevation of plasma LDL levels can be caused by two factors, first, a decrease in the clearance of LDL and second, an overproduction of this lipoprotein. Catabolism of LDL is largely determined by the LDL receptors as clearly shown in patients with familial hypercholesterolemia (FH). In this inherited disease the patients do not have normal LDL receptors and their LDL levels are remarkably elevated. LDL production is also increased in these subjects. In the rest of the population LDL levels are regulated by both the LDL clearance and production rate. The latter also seems to be related to the LDL receptor activity. The conversion of the LDL precursor, very low density lipoprotein (VLDL) to LDL is the most important factor regulating LDL synthesis. When the LDL receptor activity is low a large fraction of VLDL apolipoprotein B (apoB), the major structural protein in VLDL, is converted to LDL, and LDL production is high. On the other hand, only a small part of VLDL apoB is converted to LDL resulting in low LDL synthesis rate in conditions with high LDL receptor activity. The relationships between production and clearance of LDL are, however, more complex. There are individuals who produce a large number of VLDL and LDL particles but maintain LDL concentrations at a normal level by clearing their LDL very effectively. These subjects obviously have another abnormality in lipoprotein metabolism namely an overproduction of apoB. This disorder has been observed in several conditions like obesity, adult-onset diabetes mellitus, several patients with familial combined hyperlipidemia and some normolipidemic subjects with premature coronary heart disease. In all these conditions increased transport of LDL can be associated with coronary artery disease even in the absence of hypercholesterolemia. This raises the possibility that increased flux of LDL could itself be atherogenic possibly by overloading reverse cholesterol transport. Finally, there is some evidence that LDL particle composition may be important in the process of atherogenesis. High LDL apoB but normal LDL cholesterol levels, hyperapobetalipoproteinemia, has been associated with premature coronary heart disease.(ABSTRACT TRUNCATED AT 400 WORDS)