👤 Masami Sairyo

We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions. This study aimed to investigate the protein composition of HDL particles in patients with CETP-D. Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL. We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P < .001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P < .01). We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D. Show less

Fasting and postprandial hypertriglyceridemia (PHTG) are caused by the accumulation of triglyceride (TG)-rich lipoproteins and their remnants, which have atherogenic effects. Fibrates can improve fasting and PHTG; however, reduction of remnants is clinically needed to improve health outcomes. In the current study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), K-877 (Pemafibrate), on PHTG and remnant metabolism. Male C57BL/6J mice were fed a high-fat diet (HFD) only, or an HFD containing 0.0005% K-877 or 0.05% fenofibrate, from 8 to 12 weeks of age. After 4 weeks of feeding, we measured plasma levels of TG, free fatty acids (FFA), total cholesterol (TC), HDL-C, and apolipoprotein (apo) B-48/B-100 during fasting and after oral fat loading (OFL). Plasma lipoprotein profiles after OFL, which were assessed by high performance liquid chromatography (HPLC), and fasting lipoprotein lipase (LPL) activity were compared among the groups. Both K-877 and fenofibrate suppressed body weight gain and fasting and postprandial TG levels and enhanced LPL activity in mice fed an HFD. As determined by HPLC, K-877 and fenofibrate significantly decreased the abundance of TG-rich lipoproteins, including remnants, in postprandial plasma. Both K-877 and fenofibrate decreased intestinal mRNA expression of ApoB and Npc1l1; however, hepatic expression of Srebp1c and Mttp was increased by fenofibrate but not by K-877.Hepatic mRNA expression of apoC-3 was decreased by K-877 but not by fenofibrate. K-877 may attenuate PHTG by suppressing the postprandial increase of chylomicrons and the accumulation of chylomicron remnants more effectively than fenofibrate. Show less

We previously reported that patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) have a higher prevalence of atherosclerotic cardiovascular disease, in spite of increased HDL-C levels. However, characterization of HDL in CETP-D has not been well described. Therefore, we examined HDL particle number (PN) rather than HDL-C level. Nine patients with CETP-D and 9 normolipidemic subjects were enrolled. We performed gel permeation high-performance liquid chromatography (GP-HPLC) analysis, determined the cholesterol and triglyceride composition of all lipoprotein subclasses, and calculated the PN of each subclass, which consisted of 3 VLDL (large, medium, and small), 4 LDL (large, medium, small, and very small), and 5 HDL (very large, large, medium, small, and very small) subclasses. The PNs of large and medium LDL were significantly lower in CETP-D than that in healthy subjects (0.66- and 0.63-fold decrease, respectively; p<0.001), whereas the PN of very small LDL, which is known to be atherogenic, was significantly higher (1.36-fold increase, p = 0.016). The PNs of very large and large HDL in CETP-D were markedly higher than that in healthy subjects (19.9- and 4.5-fold increase, respectively; p<0.001), whereas the PNs of small and very small HDL, which have more potent anti-atherogenic functions, were significantly lower (0.76- and 0.61-fold decrease, respectively; p<0.001). We have assessed the PNs of detailed subclasses of patients with CETP-D for the first time. The PN of larger HDL was markedly increased, that of smaller HDL was decreased, and that of very small LDL was increased, suggesting that CETP-D has pro-atherogenic lipoprotein properties. Show less