ATHEROGENIC, DENSE LOW-DENSITY LIPOPROTEINS - PATHOPHYSIOLOGY AND NEWTHERAPEUTIC APPROACHES

It is well established that elevated circulating concentrations of cho lesterol-rich. low-density lipoproteins (LDL) represent a major risk f actor for the premature development of coronary artery disease. Only r ecently, however, has attention been drawn to the relationship between the qualitative features of plasma LDL particles and cardiovascular r isk, particularly in view of the frequent occurrence of increased leve ls of dense, small LDL in coronary artery disease patients. Combined h yperlipidaemia, a frequent form of dyslipidaemia which is associated w ith premature atherosclerosis, is characterized by elevated plasma con centrations 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 LD L 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 potentia ted as a result of retention in the arterial intima upon binding to ex tracellular matrix components and exposure to oxidative stress, leadin g to uptake by macrophages with subsequent foam cell formation. Such c holesterol-loaded, macrophage foam cells are active secretory cells, a nd exert multiple proinflammatory, proatherogenic and prothrombogenic effects during the initiation and progression of atherosclerotic plaqu es. Indeed, the secretory products of foam cells play a key role in th e fragilization of lipid-rich plaques, leading ultimately to plaque ru pture and the associated thrombotic complications. As the pharmacologi cal modulation of dense LDL levels is of special interest, representin g a new therapeutic approach in the treatment of atherogenic dyslipida emia, we probed the biological mechanisms which underlie formation of dense LDL particles in combined hyperlipidaemia patients with a fibrat e derivate, fenofibrate. Drug treatment (micronized fenofibrate, 300 m g.day(-1) for 8 weeks) induced significant reductions in the plasma co ncentrations 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 H DL to atherogenic, apolipoprotein B-containing lipoproteins (VLDL and LDL) revealed marked reduction (-38%) in cholesterol ester transfer fr om HDL to VLDL upon fenofibrate treatment, whereas no modification in the low rate of cholesteryl ester transfer between HDL and LDL was det ected. Simultaneously. however, the LDL profile in combined hyperlipid aemia patients, which is characterized by a predominance of small, den se LDL, was shifted towards the LDL subpopulation of intermediate dens ity and larger size. Particles of the intermediate LBL subclass are av idly bound and degraded by the cellular LBL receptor which represents the major, non-atherogenic pathway for catabolism of LDL-cholesterol. Our findings indicate that the overall mechanism of the fenofibrate-in duced modulation of the atherogenic dense LDL profile in combined hype rlipidaemia involves reduction in cholesteryl ester transfer from HDL to VLDL together with normalization of the intravascular transformatio n of hepatic VLDL to receptor-active LDL of intermediate density.