Hyperlipidemias: Japan

Shiomi M, Fan J. · Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Hyogo, Japan. · Curr Opin Lipidol. · Pubmed #18957890 No free full text.

Abstract: PURPOSE OF REVIEW: Use of suitable animal models is essential for investigation of the mechanisms underlying cardiac events and development of the therapeutic strategies; however, ideal animal models that can recapitulate human coronary atherosclerosis and subsequent acute myocardial infarction are still lacking. In this article, we review the insights learned from myocardial infarction-prone Watanabe heritable hyperlipidemic (designated as WHHLMI) rabbits and discuss the possibility of using this model for the study of human acute coronary syndromes. RECENT FINDINGS: The vulnerable plaques of human coronary arteries are histologically characterized by a large lipid core and a thin fibrous cap with inflammatory cells. Recent studies have revealed that inflammatory cells and inflammatory mediators (such as cytokines and matrix metalloproteinases) play an important role in the plaque rupture. SUMMARY: We developed the WHHLMI rabbit that shows spontaneous myocardial infarction caused by coronary atherosclerosis. The coronary lesions of WHHLMI rabbits have features of fatty streaks, fibrous plaques, and fibroatheromatous plaques. Some plaques contain a lipid core and a thin fibrous cap similar to human vulnerable plaques. In spite of this, the plaque rupture is not observed in WHHLMI rabbits, suggesting that other additional factors such as mechanical stress are required to trigger the rupture. WHHLMI rabbits may become an important means for elucidating the possible mechanisms of plaque rupture by exposing the plaques to additional risk factors beyond hyperlipidemia.

Hishida T. · Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nizuho-ku, Nagoya City, Japan. · Yakugaku Zasshi. · Pubmed #17202793 links to  free full text

This publication has no abstract.

Doi K, Ishida K. · Nippon Institute for Biological Science, Shin-Machi, Ome, Tokyo 198-0024, Japan. · J Toxicol Sci. · Pubmed #19182431 links to  free full text

Abstract: Certain disease conditions can modify drug-induced toxicities, which, in turn, may cause a medication-related health crisis. Therefore, preclinical investigations into the alterations in drug-induced toxicities using appropriate disease animal models are very important. This paper reviews the reported data related to the effects of diabetes and hypertriglyceridemia, common lifestyle-related diseases in a modern society, on acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity in rats and mice. It has generally been reported that diabetes protects rats and mice from APAP-induced hepatotoxicity and there are several reports that help to speculate on the effects of diabetes on APAP-induced nephrotoxicity. In fructose-induced hypertriglyceridemic rats, hepatotoxicity of APAP becomes apparently less severe, whereas nephrotoxicity of APAP becomes significantly more severe. The mechanisms of alteration of APAP-induced hepatorenal toxicity under diabetic and hypertriglyceridemic conditions are also discussed in this paper.

Ichinose A. · Department of Molecular Patho-Biochemistry and Patho-Biology on Blood and Circulation, Yamagata University School of Medicine, 2-2-2 lIida-nishi, Yamagata 990-9585, Japan. · Brain Nerve. · Pubmed #19069164 No free full text.

Abstract: Prothrombotic and proatherogenic risk factors, including elevated lipoprotein (a), predispose an individual to initial and recurrent ischemic stroke. An increased plasma level of lipoprotein (a), over 25-30 mg/dL, is called hyperlipoprotein (a)-emia, and is largely determined by genetic polymorphisms in apolipoprotein (a). Apolipoprotein (a) is a major protein component of lipoprotein (a), and is connected with apolipoprotein B-100 of low density lipoprotein. The size of apolipoprotein (a) and concentration of lipoprotein (a) vary widely among individuals as well as between ethnic groups. The size of apolipoprotein (a) and plasma concentrations of lipoprotein (a) are inversely related. Accordingly, the number of tandemly repeated structures, named kringle-4 domains, determines the size of apolipoprotein (a), and consequently the plasma lipoprotein (a) level. In addition, the efficiency of apolipoprotein (a) gene expression is a determinant of lipoprotein (a) concentrations, since lipoprotein (a) levels vary more than 200-fold even among the individuals having the same apolipoprotein (a) size. First, we identified haplotypes in the 5'-promoter region of the apolipoprotein (a) gene as a regulating factor of plasma lipoprotein (a) levels. Second, a pentanucleotide repeat polymorphism upstream of the promoter region was also reported to affect plasma lipoprotein (a) levels. Third, two functional single nucleotide polymorphisms were identified in a distal enhancer region situated approximately 20 kb from the apolipoprotein (a) gene. Finally, several polymorphisms were identified in the kringle-4 domains, and found to influence plasma lipoprotein (a) levels as well as the lysine/fibrin-binding function. Since lower molecular weight forms of apolipoprotein (a) are closely associated with the incidence of ischemic stroke, both high plasma concentrations of lipoprotein (a) and small sizes (i. e., number of kringle-4 repeats in the gene) of apolipoprotein (a) are risk factors for the development of atherothrombosis.

Kuroki A, Akizawa T. · Department of Nephrology, Showa University, School of Medicine. · Nippon Rinsho. · Pubmed #18788403 No free full text.

Abstract: Intraglomerular hypertension, and glomerular hypertrophy, leading to glomerular scarring are suggested to have an effect on the progression in chronic kidney disease, unrelated to the initial cause of kidney injury. Tubulointerstitial disease is another factor, which may affect the prognosis. Strategies to prevent or minimize the progression of kidney disease consist of treating these disease-worsening mechanisms, including smoking cessation, treatment of hyperlipidemia, sodium and protein restriction, antihypertensive therapy, inhibition of renin-angiotensin-aldosterone system, and treatment of anemia. Studies in experimental animals and humans suggest that these therapies are effective to prevent the progression in chronic kidney disease and there are some evidences that these therapies have benefits in the patients with chronic kidney disease.

Saruta T. · Keio University. · Nippon Rinsho. · Pubmed #18700540 No free full text.

Abstract: Mild hypertension is defined as blood pressure level of 140-159 mmHg systolic and/or 90-99 mmHg diastolic. The patients with blood pressure level of mild hypertension occupy about 60% of total hypertensive patients in Japan, and most of them are free of subjective symptoms except elevated blood pressure. However, some of the patients with mild hypertension develop cardiovascular events, since thay have occasionally cardiovascular damages on this level of blood pressure and several risk factors of cardiovascular diseases such as diabetes mellitus and hyperlipidemia.

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.

Du XM, Irino N, Furusho N, Hayashi J, Shoyama Y. · Seiwa Pharmaceuticals Ltd., 1-12-15 Shiba-Daimon, Minato-ku, Tokyo, 105-8585, Japan. · Nat Med (Tokyo). · Pubmed #18404313 No free full text.

Abstract: The extract of Anoectochilus formosanus showed significant activity in decreasing the levels of the cytosolic enzymes LDH, GOT, and GPT, and the result demonstrated that A. formosanus possessed prominent hepatoprotective activity against CCl(4)-induced hepatotoxicity. Moreover, in the results of the test using aurothioglucose-induced obese mice, the extract showed a significant antihyperliposis effect. A. formosanus grown in the wild and propagated by tissue culture contain ten compounds, including a major known component, (3R)-3-(beta-D-glucopyranosyloxy)butanolide (kinsenoside; 1), and two new components, (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanoic acid (2) and 2-[(beta-D-glucopyranosyloxy)methyl]-5-hydroxymethylfuran (3), along with the known compounds, isopropyl-beta-D-glucopyranoside (4), (R)-3,4-dihydroxybutanoic acid gamma-lactone (5), 4-(beta-D-glucopyranosyloxy) benzyl alcohol (6), (6R,9S)-9-(beta-D-glucopyranosyloxy)megastigma-4,7-dien-3-one (7), and (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanolide (8). Since a higher concentration of kinsenoside (1) was detected in the crude drugs A. formosanus and A. koshunensis by high-performance liquid chromatography (HPLC) analysis, we proved a simple purification system for kinsenoside (1), giving 180 mg of kinsenoside (1) from 1 g of dried samples for further pharmacological experiments. In an anti-hyperliposis assay using high-fat-diet rats, 1 significantly reduced the weights of the body and the liver, and also decreased the triglyceride level in the liver compared to those of control rats. On the other hand, the epimer of 1, (3S)-3-(beta-D-glucopyranosyloxy)butanolide, goodyeroside A (9), which was isolated from the Goodyera species, had no effect for anti-hyperliposis. In aurothioglucose-induced obese mice, 1 suppressed the body and liver weight increase, significantly ameliorated the triglyceride level in the liver, and also reduced the deposition of uterine fat pads. The anti-hepatoxic activities of 9 and goodyerosides B (10) were studied on injury induced by CCl(4) in primary cultured rat hepatocytes by measuring the levels of LDH, GOT, and GPT. In the CCl(4)-treated control group, there were marked increases in LDH, GOT, and GPT activities compared with the normal group. In contrast, these levels were suppressed in 9- and 10-treated groups. Goodyerin (11), a new typical flavone glycoside, exhibited a significant and dose-dependent sedative and anticonvulsant effect.

Nadanaka S, Kitagawa H. · Department of Biochemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan. · J Biochem. · Pubmed #18367479 No free full text.

Abstract: Proteoglycans carrying heparan sulphate (HS) chains are ubiquitously expressed at cell surfaces and in extra-cellular matrices, and HS chains interact with numerous proteins, including growth factors, morphogens and extra-cellular-matrix proteins. These interactions form the basis of HS-related biological phenomena. Thus, the biosynthesis of HS regulates key events in embryonic development and homeostasis, and deranged HS biosynthesis could cause diseases. EXT1 and EXT2 genes encoding the polymerase responsible for HS biosynthesis are known as causative genes of hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by the formation of multiple cartilaginous tumours. In this review, we will summarize HS biosynthesis in several model animals, the effects on cellular functions by alteration of HS biosynthesis, and HS-associated diseases. This review suggests that HS biosynthetic enzymes would be potential candidates for drug targets in various diseases.

Ikeda I. · Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Scicence, Tohoku University, Sendai, Japan. · Asia Pac J Clin Nutr. · Pubmed #18296354 No free full text.

Abstract: Tea catechins reduce serum cholesterol concentrations and suppress postprandial hypertriacylglycerolemia in experimental animals and humans. These effects are mainly ascribed to the gallate esters of catechins, (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG). During pasteurization of tea drinks, tea catechins are epimerized to so-called heat-treated tea catechins such as (-)-catechin gallate (CG) and (-)-gallocatechin gallate (GCG). We showed that both tea catechins and heat-treated tea catechins with the galloyl moiety lowered intestinal absorption of cholesterol by inhibiting micellar solubility of cholesterol. Since they inhibited pancreatic lipase in vitro and slowed down lymphatic absorption of triacylglycerols, it is suggested that delayed intestinal absorption of triacylglycerols after the feeding of catechin preparations causes suppression of postprandial hypertriacylglycerolemia. It has been reported that tea catechins and heat-treated tea catechins with the galloyl moiety suppress deposition of visceral fat in experimental animals and humans. Some studies suggest that the stimulation of hepatic beta-oxidation might be a cause for reduced deposition of visceral fat. However, our study did not show any acceleration of beta-oxidation in rat livers. Although there are some controversial observations, results obtained suggest a possibility that tea catechins and heat-treated tea catechins with the galloyl moiety improve lipid metabolism and contribute to the prevention of the metabolic syndrome.

Kawano S, Kumagai S. · Department of Clinical Laboratory, Kobe University Hospital. · Nippon Rinsho. · Pubmed #18161157 No free full text.

This publication has no abstract.

Fukumoto Y, Shimokawa H. · Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #18074533 No free full text.

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Yanai H, Tomono Y, Ito K, Furutani N, Yoshida H, Tada N. · Department of Internal Medicine, The Jikei University School of Medicine, Chiba, Japan. · Nutr J. · Pubmed #18072966 links to  free full text

Abstract: Excess adiposity has been shown to play a crucial role in the development of the metabolic syndrome. The elevated fasting and postprandial triglyceride-rich lipoprotein levels is the central lipid abnormality observed in the metabolic syndrome. Recent studies have indicated that diacylglycerol (DAG) is effective for fasting and postprandial hyperlipidemia and preventing excess adiposity by increasing postprandial energy expenditure. We will here discuss the mechanisms of DAG-mediated improvements in hyperlipidemia and in postprandial energy expenditure, and effects of DAG oil on lipid/glucose metabolism and on body fat. Further, the therapeutic application of DAG for the metabolic syndrome will be considered.

Harada E, Yasue H, Mizuno Y, Ito T, Sakaino N, Yasue S, Masuzaki H. · Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute, 6-8-1 Yanamuro, Kumamoto City, Japan. · Am J Med Sci. · Pubmed #18030188 No free full text.

Abstract: The metabolic disorders associated with chronic hypoxemia in adult patients with tetralogy of Fallot (TOF) have not been fully appreciated. We report a 53-year-old male patient with TOF who presented with fasting hypoglycemia, hypertriglyceridemia, increased blood levels of free fatty acids, adiponectin, B-type natriuretic peptide, and uric acid. The cluster of these metabolic derangements has not been previously reported, and the possible role of chronic hypoxia in the production of these disturbances is discussed with a review of pertinent literatures.

Ito T. · Division of Cardiovascular Disease, Tokyo Teishin Hospital. · Nippon Rinsho. · Pubmed #17953022 No free full text.

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Fusazaki T. · Department of Internal Medicine II, Iwate Medical University School of Medicine and Memorial Heart Center. · Nippon Rinsho. · Pubmed #17948700 No free full text.

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Hayashi T, Yokote K, Saito Y, Iguchi A. · Nagoya University Graduate School of Medicine, Department of Geriatrics, 65 Tsuruma-cho, Showa-ku, Nagoya City, 466-8550, Japan. · Expert Opin Pharmacother. · Pubmed #17927486 No free full text.

Abstract: Pitavastatin, (+)-monocalcium bis(3R,5S,6E)-7-(2-cyclopropyl-4-[4-fluorophenyl]-3-quinolyl-3,5-dihydroxy-6-heptenoate), is a totally synthetic statin developed in Japan with a molecular weight of 880.98. Pitavastatin achieves its potent pharmacologic action by strongly binding and inhibiting the active site of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and has potent low-density lipoprotein-cholesterol-lowering effects similar to atorvastatin and rosuvastatin. One other characteristic of the agent is that pitavastatin is minimally metabolized by the cytochrome P450 isozymes; it undergoes glucuronidation and is converted to the inactive lactone form, and, therefore, the incidence of any drug interactions is reduced. Due to the promising results observed in clinical trials, it has the potential to be an excellent addition to the worldwide lipid management market.

Shimamoto K, Miura T. · Second Department of Internal Medicine, Sapporo Medical University. · Nippon Rinsho. · Pubmed #17824086 No free full text.

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Iwata F, Okada T. · Department of Pediatrics, Nihon University School of Medicine. · Nippon Rinsho. · Pubmed #17824085 No free full text.

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Hayashi T. · Department of Geriatrics, Nagoya University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #17824083 No free full text.

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Ohni M. · Department of Geriatric Medicine, Kyorin University School of Medicine. · Nippon Rinsho. · Pubmed #17824082 No free full text.

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Wakatsuki A. · Department of Obstetrics & Gynecology, Aichi Medical University. · Nippon Rinsho. · Pubmed #17824078 No free full text.

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Suzuki T, Suzuki K, Igari Y, Matsumura N, Oba K. · Department of Geriatrics, Nippon Medical School. · Nippon Rinsho. · Pubmed #17824075 No free full text.

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Yamamura T, Ishigami M. · Division of Health Sciences, Osaka University Graduate School of Medicine. · Nippon Rinsho. · Pubmed #17824071 No free full text.

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Ohni M. · Department of Geriatric Medicine, Kyorin University School of Medicine. · Nippon Rinsho. · Pubmed #17824065 No free full text.

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