Hyperlipidemias: Saku K

Miura S, Saku K. · No affiliation provided · Intern Med. · Pubmed #17409593 links to  free full text

This publication has no abstract.

Miura S, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. · Intern Med. · Pubmed #18591835 links to  free full text

Abstract: Niemann-Pick C1-like 1 (NPC1L1) has recently been identified and has been shown to have features of a plasma membrane transporter, including a secretion signal, 13 predicted transmembrane domains, extensive N-linked glycosylation sites and a sterol-sensing domain. It is highly expressed on the surface of absorptive jejunal enterocytes. NPC1L1 has been shown to be a direct target of ezetimibe, and an ezetimibe-sensitive pathway plays a role in intestinal cholesterol absorption. Ezetimibe-based therapy represents an exciting new area in the treatment of dyslipidemia.

Zhang B, Noda K, Matsunaga A, Kumagai K, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. · J Atheroscler Thromb. · Pubmed #15725695 links to  free full text

Abstract: This study compared the effects of fluvastatin and pravastatin on the in vivo oxidation of LDL in a crossover design to evaluate whether or not it is justified to switch between the two statins with regard to serum levels of lipids, lipoproteins, and apolipoproteins (apo), and circulating autoantibodies to oxidized LDL (OxLDL-Ab). Patients with hypercholesterolemia (n = 46) were randomly assigned into groups who received fluvastatin (20 mg/d) or pravastatin (10 mg/d). After 3 months, they were crossed to receive the other statin for another 3 months. Circulating levels of OxLDL-Ab were measured by an OxLDL IgG ELISA test. Fluvastatin and pravastatin similarly decreased serum levels of total cholesterol (TC), LDL-C, and apo B, and increased HDL(2)-C levels. After crossover to the other statin, these lipid parameters were not further changed by either statin. Before crossover, circulating levels of OxLDL-Ab were decreased in patients with fluvastatin treatment, but not in those with pravastatin treatment. After switching from the other statin, both fluvastatin and pravastatin further decreased OxLDL-Ab levels. In conclusion, fluvastatin at 20 mg/d and pravastatin at 10 mg/d are similar with regard to their efficacy in decreasing TC, LDL-C, and apo B levels and increasing HDL(2)-C levels. Fluvastatin lowered circulating levels of OxLDL-Ab, and these effects continued after switching to pravastatin.

Bai H, Liu R, Liu Y, Saku K, Liu BW. · Unit of Laboratory Medicine, West China Second [corrected] Hospital, Sichuan University, Chengdu, Sichuan, PR of China. · Acta Cardiol. · Pubmed #18664021 No free full text.

Abstract: OBJECTIVES: Hypertriglyceridaemia has been recognized as an independent risk factor for the development of coronary heart disease. Apolipoprotein A-IV (apo A-IV) plays an important role in the metabolism of TG-rich lipoproteins and HDL. However, the role of the polymorphism of the apo A-IV gene in hyperlipidaemia remains to be fully determined. The impact of the genetic variant in the apolipoprotein A-IV gene on lipid risk factor profiles for coronary heart disease was examined in Chinese patients with type-IV hyperlipoproteinaemia (HTG) and in healthy control individuals. METHODS: We genotyped five polymorphisms in the apo A-IV gene (codon 9, codon 347, codon 360, 3'end VNTR and Msp I sites) by direct sequencing or RFLP analysis in a Chinese population. RESULTS: The genotype frequencies in our results were significantly different from those reported in Caucasians. The polymorphic sites of codon 347 and codon 360, that have been widely studied in Western populations, were not observed in our population. The frequency of the G allele at codon 9 in HTG subjects was higher than that in healthy controls (P < 0.05). Serum apolipoprotein A-I (apo A-I), triglyceride (TG) and low-density lipoprotein cholesterol (LDLC) levels were affected by genotypes of codon 9, Msp I and VNTR polymorphisms, respectively, with some sex-specific effects in the control or HTG group. CONCLUSION: These results suggest that codon 9, Msp I and VNTR polymorphisms in the apo A-IV gene are associated with type-IV hyperlipoproteinaemia in a Chinese population.

Iwata A, Miura S, Imaizumi S, Zhang B, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Fukuoka. · J Cardiol. · Pubmed #17987838 No free full text.

Abstract: OBJECTIVES: Atherosclerotic changes in the rabbit have been evaluated by various methods. Although most previous studies have analyzed atherosclerotic plaque in the femoral, carotid and iliac arteries of rabbits by intravascular ultrasound (IVUS) because of easier access, we established a method for the precise measurement of plaque volume as well as plaque area in the thoracic descending aorta in the Watanabe heritable hyperlipidemic (WHHL) rabbit, which has severe atherosclerosis. METHODS: WHHL and Japanese White (JW)rabbits were used. An IVUS catheter was inserted into the right femoral artery and advanced to the left subclavian artery, which was used as an anatomical landmark. After IVUS image acquisition, the catheter was removed. Vessel volume, lumen volume and plaque volume were analyzed. RESULTS: Atheroma of the aorta was easily detected in WHHL rabbits by IVUS examination, whereas atherosclerosis was not observed in JW rabbits. The atheroma showed a low-echoic lesion compared to the adventitia, with morphological characteristics similar to human lipid-rich, soft atheromatous plaques. In 15-month-old WHHL rabbits, the vessel volume, lumen volume and plaque volume in the thoracic descending aorta were 815 +/- 109, 559 +/- 107 and 256 +/- 10 mm3/ 3 cm, respectively. CONCLUSIONS: We established a method for the precise quantitation of plaque volume by IVUS technology in WHHL rabbits aorta for the first time. This method is useful for evaluating several locally or generally delivered therapeutic agents in a hyperlipidemic animal model.

Matsunaga A, Arishima H, Niimura H, Zhang B, Uehara Y, Ohwaki K, Morita M, Hayashida K, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Johnan-ku, Fukuoka, Japan. · Circ J. · Pubmed #17457003 links to  free full text

Abstract: BACKGROUND: The apolipoprotein A5 gene (ApoA5) plays an important role in modulating triglyceride metabolism. Polymorphisms of ApoA5, including -1131T>C and c.553G>T (G185C), have been reported to correlate with hypertriglyceridemia (HTG). In the present study the relationships of 5 single nucleotide polymorphisms, including the -1131T>C, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C polymorphisms of ApoA5, with HTG were investigated. METHODS AND RESULTS: The study group comprised 95 Japanese patients with HTG and 119 unrelated normolipidemic subjects. Frequencies of the C allele of -1131T>C (0.511) and the T allele of c.553G>T (0.205) in the hypertriglyceridemic patients were significantly higher than in the normolipidemic subjects (0.315 and 0.105, respectively). The c.56C>G (S19W) polymorphism was not observed, and the other 4 polymorphic sites were in strong linkage disequilibrium. Five of the 8 detected haplotypes with the C allele of -1131T>C correlated with HTG. Promoter activities of ApoA5, including that with the -1131T>C polymorphism, were estimated using a luciferase assay. Analysis of ApoA5 promoters showed that the -1131T>C polymorphism alone had no effect. Comparison of expression of mutant G185C and wild-type ApoA5-green fluorescent protein (GFP) in HepG2 cells showed that ApoA5-GFP was abundant in punctate endosome-like structures, and ApoA5 (G185C)-GFP expression resembled that of the wild type. CONCLUSIONS: The -1131T>C and c.553G>T (G185C) polymorphisms correlated with HTG in this Japanese population, but neither polymorphism directly affected ApoA5 expression.

Kiya Y, Miura S, Zhang B, Urata H, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Japan. · Endocr J. · Pubmed #17001111 links to  free full text

Abstract: The patient was a 51-year-old Japanese female who had been diagnosed with hyperlipidemia. At the first medical examination, her serum levels of total cholesterol (TC) and triglyceride (TG) were 482 and 205 mg/dl, respectively. Since hyperlipidemia was not improved by pravastatin, atorvastatin or niceritrol, and since the levels of thyroid-stimulating hormone (TSH) and free T4 were 730 IU/ml and 0.3 ng/dl, respectively, the patient was diagnosed as secondary hyperlipidemia with hypothyroidism. A method for the charge isolation of lipoproteins using capillary isotachophoresis (cITP) is proposed as a clinical application because it allows us to quantitatively measure electronegative low-density lipoprotein cholesterol (LDL-C), a potent marker of coronary heart disease. After 5 months of treatment with levothyroxine, Serum TC and LDL-C levels drastically decreased without statin treatment and high-density lipoprotein cholesterol (HDL-C) increased. In the lipoprotein profiles as assessed by cITP after treatment with levothyroxin, all HDL-C subfractions were increased and fast-migrating LDL/electronegative LDL appeared to be greatly reduced after treatment, while the area under the non-modified LDL peak was increased. The cITP analysis was able to obtain more information about coronary risk factors and may be clinically useful for evaluating the effect of treatment with levothyroxine in patients with hypothyroidism and secondary hyperlipidemia.

Zhang B, Katafuchi R, Arishima H, Matsunaga A, Rye KA, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan. · Clin Chim Acta. · Pubmed #16806136 No free full text.

Abstract: BACKGROUND: The present study examined the effects of atorvastatin and the in vitro effect of apolipoprotein (apo) A-I/phosphatidylcholine (POPC) discs on charge-based triglyceride-rich lipoprotein (TRL) subfractions in a patient with type III hyperlipoproteinemia (HLP) and the apoE2/2 phenotype. METHODS: Charge-based lipoprotein subfractions were characterized by capillary isotachophoresis (cITP). cITP analysis was performed using plasma that had been prestained with a lipophilic dye on a Beckman P/ACE MDQ system. RESULTS: Treatment with atorvastatin for 4 weeks markedly decreased the slow (s)-migrating TRL subfraction and both fast- and slow-migrating low-density lipoprotein (LDL) subfractions, but did not affect the fast (f)-migrating TRL subfraction in this patient. ApoA-I/POPC discs consisted of two major charge-based subfractions that had the mobility of cITP fTRL and sTRL. Incubation of plasma from this patient in the presence of apoA-I/POPC discs caused not only a reduction in cITP fast- and intermediate-migrating HDL and an increase in cITP sHDL but also a reduction in fTRL and sTRL and an increase in sLDL. CONCLUSION: Atorvastatin and apoA-I/POPC discs decreased cITP TRL subfractions in a complementary manner, suggesting that the combination of apoA-I/POPC discs and atorvastatin could be a promising therapeutic approach for hypertriglyceridemia.

Zhang B, Böttcher A, Imaizumi S, Noda K, Schmitz G, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. · Atherosclerosis. · Pubmed #16620837 No free full text.

Abstract: OBJECTIVE: Both mildly modified LDL subfraction that carries a more-negative electric charge and remnant-like particles (RLP) are closely related to triglyceride (TG) levels. We examined the relation between the RLP-cholesterol (C) level and charge-based apolipoprotein (apo) B-containing lipoprotein subfractions as determined by capillary isotachophoresis (cITP) in patients with hypercholesterolemia. METHODS AND RESULTS: cITP apo B lipoprotein subfractions were identified by analyzing plasma depleted of the related lipoproteins. While fast-migrating triglyceride-rich lipoprotein (fTRL) subfraction contained both chylomicrons and VLDL fraction, slow TRL (sTRL) only contained VLDL. cITP fLDL also contained VLDL fraction, i.e., beta-VLDL. Levels of cITP fTRL and sTRL were significantly correlated with serum levels of TG, RLP-C, apo C-II, and C-III. Levels of cITP sTRL were also correlated with apo E. Levels of cITP fLDL were positively correlated with not only LDL-C levels but also levels of TG, RLP-C, apo C-II, C-III, and E. CONCLUSION: cITP fast LDL correlated with RLP-C levels and modified the relation between RLP-C and TG levels.

Noda K, Zhang B, Uehara Y, Miura S, Matsunaga A, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Japan. · Circ J. · Pubmed #16308511 links to  free full text

Abstract: BACKGROUND: The potency and usefulness of capillary isotachophoresis (cITP) for assessing whole-serum lipoprotein profiles and quantifying electronegative low-density lipoprotein (LDL) has been previously reported. METHODS AND RESULTS: A new cITP method to measure electronegative LDL in the small dense LDL fraction has been established. Both electronegative LDL and electronegative LDL in the small dense LDL fraction decreased after treatment with fenofibrate. CONCLUSIONS: This method appears to be useful for analyzing a marker of coronary heart disease risk and may be suitable for evaluating the effects of hypolipidemic agents.

Zhang B, Kaneshi T, Ohta T, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. bozhang @fukuoka-u.ac.jp · J Lipid Res. · Pubmed #16061945 links to  free full text

Abstract: The proportion of the electronegative low density lipoprotein [LDL(-)] subfraction, which is atherogenic, is increased in type 2 diabetes but is not reduced by glycemic control. Therefore, we evaluated the ability of a new technique, capillary isotachophoresis (cITP), to quantify charge-based LDL subfractions and examined the relation between insulin resistance and the cITP fast-migrating (f) LDL levels. Seventy-five 10-year-old boys were included. The two cITP LDL subfractions, fLDL and major LDL subfractions, were proportional to the LDL protein content within the range of 0.1-0.8 mg/ml LDL protein. Levels of cITP fLDL were positively correlated with triglyceride (TG) levels and negatively correlated with LDL size. Insulin resistance as assessed by the homeostasis model assessment (HOMA-IR) was positively correlated (P < 0.01) with cITP fLDL levels (r = 0.41). The relation between HOMA-IR and cITP fLDL levels depended on TG levels but was independent of body mass index and LDL size. cITP lipoprotein analysis is an accurate and sensitive method for quantifying charge-based LDL subfractions in human plasma, and insulin resistance is related to cITP fLDL independent of LDL size.

Okura Y, Hayashi K, Shingu T, Kajiyama G, Nakashima Y, Saku K. · Division of Cardiology, Department of Internal Medicine, Fukuoka Dental College Hospital, 2-15-1, Tamura, Sawara-ku, Fukuoka 814-0193, Japan. · World J Gastroenterol. · Pubmed #15534935 links to  free full text

Abstract: We present two diagnostically challenging cases of acute pancreatitis with hypertriglyceridemia accompanied with chylomicronemia caused with a deficiency of lipoprotein lipase and with the presence of type V hyperlipidemia. Both cases suffered from acute abdomen following the ingestion of fatty food and revealed the increase in parameters of inflammation without significant elevation of serum amylase levels. The imaging examination of ultrasonography could not detect significant findings of acute pancreatitis and a computer tomography scan eventually confirmed the findings of acute pancreatitis. Both cases responded to a low fat diet and administration of a cholecystokinin receptor antagonist, exhibiting a relief of abdominal symptoms. As in the present cases with acute abdomen following the ingestion of fatty food, the identification of serum hypertriglyceridemia and an abdominal computer tomography scan might be useful in establishing the diagnosis of acute pancreatitis and in developing the therapeutic regimen, when hypertriglyceridemia interferes with the evaluation of pancreatic enzyme activities and ultrasound examination provides poor pancreatic visualization.

Zhang B, Fan P, Tanaka H, Saku K. · Department of Internal Medicine, Fukuoka University, Japan. · Br J Biomed Sci. · Pubmed #11787997 No free full text.

Abstract: CS-866 is an angiotensin II type-1 receptor antagonist, the effects of which on systolic blood pressure (BP) and glucose/insulin metabolism are investigated under hyperlipidaemic conditions produced by cholesterol feeding. Thirty-two female Japanese White rabbits (two months old) were assigned randomly into a CS-866-treated group (n = 17) fed a food admixture that contained 0.03% CS-866 and 0.2% cholesterol, or into a control group (n = 15) fed a food admixture containing 0.2% cholesterol only. Systolic BP was measured by an ear-cuff method. Glucose and insulin metabolism was characterised quantitatively from the results of an intravenous glucose tolerance test by a minimal model technique reported previously. After six months treatment, systolic BP in the CS-866-treated group was lower than in the control group (105 +/- 14 mmHg versus 115 +/- 18 mmHg; P <0.05), as assessed by analysis of variance and the Wilcoxon rank-sum test. No significant differences were seen in plasma aldosterone concentration, plasma renin activity, or angiotensin-converting enzyme activity between the groups. Administration of CS-866 for six months did not affect either glucose tolerance or insulin sensitivity. Other model parameters such as basal (steady-state) insulin and glucose concentration, first- and second-phase post-hepatic insulin delivery to glucose, and insulin clearance rate constant were unaffected. In conclusion, CS-866 treatment reduced systolic BP without affecting glucose/insulin metabolism under hyperlipidaemic conditions produced by cholesterol feeding.

Zhang B, Shiomi M, Tanaka H, Mei J, Fan P, Tsujita Y, Horikoshi H, Saku K. · Department of Internal Medicine, Fukuoka University, Japan. · Eur J Drug Metab Pharmacokinet. · Pubmed #11695719 No free full text.

Abstract: To clarify the dose-response effects of troglitazone on insulin sensitivity and beta-cell function, we examined the effects of high-dose troglitazone (100 mg/day per animal, administered as a food admixture) on glucose and insulin metabolism in hyperinsulinemic Watanabe heritable hyperlipidemic (WHHL) rabbits, and compared the results with our previous results with low-dose troglitazone (10 mg /day per animal). MATERIALS AND METHODS: Glucose and insulin metabolism were quantitatively characterized by a minimal model technique as reported previously. RESULTS: When troglitazone was administrated at a high dose for 6 months, it reduced hyperinsulinemia as reflected by a reduced basal (steady-state) insulin concentration lb and the insulin response to a glucose load, improved beta-cell function as reflected by decreased second-phase post-hepatic insulin delivery to glucose phi2, and reduced insulin resistance as reflected by increased insulin sensitivity to glucose disposal Si, without affecting glucose tolerance as reflected by an unchanged rate of glucose utilization Kg or insulin-independent glucose disposal Sg. The reductions in Ib and phi2 and the increases in Si in WHHL rabbits treated with a high dose of troglitazone were greater (p<0.05) than those observed in WHHL rabbits treated with a low dose of troglitazone, as assessed by a two-way repeated measures analysis of variance and the Wilcoxon-Mann-Whitney test. CONCLUSION: In WHHL rabbits, troglitazone dose-dependently reduced hyperinsulinemia, improved beta-cell function, and increased insulin sensitivity.