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.