Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches

Abstract

It is well established that elevated circulating concentrations of cholesterol-rich, low-density lipoproteins (LDL) represent a major risk factor for the premature development of coronary artery disease. Only recently, however, has attention been drawn to the relationship between the qualitative features of plasma LDL particles and cardiovascular risk, particularly in view of the frequent occurrence of increased levels of dense, small LDL in coronary artery disease patients. Combined hyperlipidaemia, a frequent form of dyslipidaemia which is associated with premature atherosclerosis, is characterized by elevated plasma concentrations of both triglyceride-rich, very-low-density lipoproteins (VLDL) and LDL. In combined hyperlipidaemia patients, small, dense LDL (d 1.04-1.06 g.ml-1) predominate over the light (d 1.02-1.03 g.ml-1) and intermediate (d 1.03-1.04 g.ml-1) LDL subpopulations. Dense LDL are highly atherogenic as a result of their low binding affinity for the LDL receptor, their prolonged plasma half-life and low resistance to oxidative stress. Biological modification of dense LDL is potentiated as a result of retention in the arterial intima upon binding to extracellular matrix components and exposure to oxidative stress, leading to uptake by macrophages with subsequent foam cell formation. Such cholesterol-loaded, macrophage foam cells are active secretory cells, and exert multiple proinflammatory, proatherogenic and prothrombogenic effects during the initiation and progression of atherosclerotic plaques. Indeed, the secretory products of foam cells play a key role in the fragilization of lipid-rich plaques, leading ultimately to plaque rupture and the associated thrombotic complications. As the pharmacological modulation of dense LDL levels is of special interest, representing a new therapeutic approach in the treatment of atherogenic dyslipidaemia, we probed the biological mechanisms which underlie formation of dense LDL particles in combined hyperlipidaemia patients with a fibrate derivate, fenofibrate. Drug treatment (micronized fenofibrate, 200 mg.day-1 for 8 weeks) induced significant reductions in the plasma concentrations of VLDL (-37%; P < 0.005), and of dense LDL (-21.5%; P < 0.05), with simultaneous increase in HDL-cholesterol (+19%; P < 0.0001). An endogenous assay of cholesteryl ester transfer from cardioprotective HDL to atherogenic, apolipoprotein B-containing lipoproteins (VLDL and LDL) revealed marked reduction (-38%) in cholesterol ester transfer from HDL to VLDL upon fenofibrate treatment, whereas no modification in the low rate of cholesteryl ester transfer between HDL and LDL was detected. Simultaneously, however, the LDL profile in combined hyperlipidaemia patients, which is characterized by a predominance of small, dense LDL, was shifted towards the LDL subpopulation of intermediate density and larger size. Particles of the intermediate LDL subclass are avidly bound and degraded by the cellular LDL receptor which represents the major, non-atherogenic pathway for catabolism of LDL-cholesterol. Our findings indicate that the overall mechanism of the fenofibrate-induced modulation of the atherogenic dense LDL profile in combined hyperlipidaemia involves reduction in cholesteryl ester transfer from HDL to VLDL, together with normalization of the intravascular transformation of hepatic VLDL to receptor-active LDL of intermediate density.