Oxidized phospholipids (OxPLs) on apolipoprotein B-100 (apoB-100) particles are strongly associated with lipoprotein [a] (Lp[a]). In this study, we evaluated whether Lp[a] is preferentially the carrier of OxPL in human plasma. The content of OxPL on apoB-100 particles was measured with monoclonal antibody E06, which recognizes the phosphocholine (PC) headgroup of oxidized but not native phospholipids. To assess whether OxPLs were preferentially bound by Lp[a] [a] and cysteine 4326 of apolipoprotein B-100 (apoB-100) form a disulfide bond to create an Lp[a] particle (2-6). The clinical interest in Lp[a] emanates from its association with cardiovascular disease (CVD) when present in high plasma concentrations. A meta-analysis of prospective studies demonstrated that elevated levels of Lp[a] are an independent risk factor for CVD (7). The pro-atherogenic influence of Lp[a] seems to be particularly enhanced in subjects with elevated levels of LDL cholesterol (8, 9).The gene for apo [a] appeared recently on the evolutionary scale and is present only in humans and nonhuman primates. An unrelated apo[a]-like gene consisting only of KIII repeats is also present in hedgehogs and is postulated to have evolved independently through divergent evolution (10). The physiological role of Lp[a] and the underlying mechanisms through which it contributes to CVD are unknown. One hypothesis suggests that Lp[a] promotes thrombosis by inhibiting thrombolysis. Apo [a] has

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (−41%), remnant cholesterol (−55%), and LDL-cholesterol (−39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.

Objective-Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. Methods and Results-We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B-containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (nϭ12) and in healthy normolipidemic control subjects (nϭ12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor-BI-and ABCG1-dependent pathways. A significant inverse relationship between scavenger receptor-BI-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.473; Pϭ0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.485; Pϭ0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein-mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. Conclusion-We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity. Key Words: ABC transporter Ⅲ lipoproteins Ⅲ macrophages Ⅲ metabolism Ⅲ receptors F amilial hypercholesterolemia (FH) is a common inherited dominant autosomal disorder caused by mutations in the gene encoding the low-density lipoprotein (LDL) receptor. 1 These mutations lead to a reduced number of functional LDL receptors, resulting in diminished cellular uptake of LDL particles, LDL accumulation, and increased plasma levels of total cholesterol, LDL cholesterol, and premature atherosclerosis. 2,3 Within the arterial wall, macrophages take up modified LDL through a variety of scavenger receptors, mainly scavenger receptor (SR)-A and CD36, accumulate cholesteryl esters (CEs), and are progressively converted into lipid-rich foam cells that represent the hallmark of the atherosclerotic plaque. 4 Excess cholesterol in macrophages is eliminated via the process of reverse cholesterol transport (RCT), a pathway by which cholesterol from peripheral tissues is transported to the liver for biliary excretion. 5 During the past few years, the atheroprotective role of RCT has been clearly demonstrated in humans. 6 The first step in this pathway is the efflux of cholesterol from cells to extracellular acceptors, such as high-density lipoprotein (HDL) and apolipoprotein AI (apoAI). Cellular cholesterol efflux to lipid-free or lipid-poor apoAI occurs through a transporter belonging to the ATP binding cassette (ABC) family, ABCA1, 7 whereas free cholesterol efflux to mature HDL particles involves both ABCG1 8 and SR-BI. 9 The low HDL cholesterol levels...