Researchers Database

ishibashi shun

    DepartmentofMedicine,DivisionofEndcrinologyandMetabolism Professor
Last Updated :2021/10/17

Researcher Information

Degree

  • PhD(The University of Tokyo)

J-Global ID

Research Interests

  • insulin   insulin   vascular biology   atherosclerosis   metabolism   glucose   lipoprotein   lipid   diabetes   

Research Areas

  • Life sciences / Metabolism and endocrinology

Academic & Professional Experience

  • 1994 - 2001  Assistant professor,
  • 2001  - professor, Division of Endocrinology and
  • 1992 - 1994  Assistant instructor,
  • 1989 - 1992  Rearch fellow,
  • 1989  Assistant professor,
  • Jichi Medical School
  • Metabolism, Department of Internal Medicine,
  • University of Tokyo
  • The 3rd Department of Internal Medicine,
  • Medical Center at Dallas
  • University of Texas Southwestern
  • Department of Molecular Genetics,
  • Medical Center at Dallas
  • University of Texas Southwestern
  • Department of Molecular Genetics,
  • University of Tokyo
  • The 3rd Department of Internal Medicine,

Education

  •        - 1982  The University of Tokyo  Faculty of Medicine  Medicine

Association Memberships

  • Japanese association of atherosclerosis   Japanese association of diabetes   Japanese association of internal medicine   

MISC

  • S Shinozaki, N Itabashi, K Rokkaku, K Ichiki, S Nagasaka, K Okada, M Fujimoto, M Ohtsuki, S Ishibashi  DIABETES RESEARCH AND CLINICAL PRACTICE  70-  (2)  183  -192  2005/11  [Not refereed][Not invited]
     
    Eruptive xanthomas in adults are usually indicative of chylomicronemia. Although diabetes mellitus is the most common secondary Cause of chylomicronemia, which is designated as diabetic lipemia, the clinical characteristics of diabetes with regard to development of xanthonias are not well defined. In this paper, we describe a young female who displayed eruptive xanthomas as an initial manifestation of diabetic lipemia. The patient was a 20-year-old female with a body mass index of 18.9 kg/m(2) and Marfanoid appearance. Her past history was unremarkable, except for patent ductus arteriosus and mild mental retardation. She was admitted to Our division for eruptive xanthomas on the extremities and marked hyperglycemia (random glucose, 520 mg/dl) and hypertriglyceridemia (6880 mg/dl). She was diagnosed with Type 2 diabetes based on the positive family history of diabetes, residual secretory capacity of insulin, and absence of autoantibodies related to Type I diabetes. Based on the increase in the concentrations of both chylomicrons and very low density lipoproteins, type V hyperlipoproteinemia was diagnosed. After the initiation of insulin therapy, both hypertriglyceridemia and eruptive xanthomas Subsided, without administering any hypolipidemic agents. Minimal model analysis of a frequently sampled intravenous glucose tolerance test revealed severe insulin resistance, despite the absence of obesity. Post-heparin lipoprotein lipase (LPL) activity was moderately decreased, and common Mutations in the LPL gene were not demonstrated by genetic screening. The apolipoprotein E phenotype was E4/4, which is known to be associated with type V hyperlipoproteinemia. Hypoadiponectinemia of 1.7 mu g/ml was also revealed, which may, in part, account for the insulin resistance and decreased LPL activity. In Conclusion, the clustering of apolipoprotein E.4/4 and hypoadiponectinemia, in addition to insulin resistance and poor glycemic control, might have resulted in hypertriglyceridemia with eruptive xanthomatosis in this Subject. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
  • M Amemiya-Kudo, J Oka, T Ide, T Matsuzaka, H Sone, T Yoshikawa, N Yahagi, S Ishibashi, J Osuga, N Yamada, T Murase, H Shimano  JOURNAL OF BIOLOGICAL CHEMISTRY  280-  (41)  34577  -34589  2005/10  [Not refereed][Not invited]
     
    Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/ E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/ E47. This synergistic activation by SREBP-1c/ BETA2/ E47 was not mediated through SREs but through the E-boxes on which BETA2/ E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c center dot BETA2 center dot E47 complex in a DNA looping structure for efficient recruitment of CREB- binding protein/ p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.
  • Y Hayashi, S Nagasaka, N Takahashi, Kusaka, I, S Ishibashi, S Numao, DJ Lee, Y Taki, H Ogata, K Tokuyama, K Tanaka  JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM  90-  (7)  4035  -4040  2005/07  [Not refereed][Not invited]
     
    Objective: Previous studies have shown that glucose effectiveness and insulin sensitivity are acutely enhanced by exercise at various intensities. The aim of this study was to determine the effects of a single bout of exercise at intensities recommended by the American Diabetes Association (ADA) and the American College of Sports Medicine (ACSM) on glucose uptake-specific glucose effectiveness (S-G(2)*) and insulin sensitivity (S-I(2)*). S-G(2)* and S-I(2)* were estimated by a two-compartment minimal model. Design: Six healthy men (age, 28.5 +/- 2.0 yr) performed a stable-labeled frequently sampled iv glucose tolerance test (FSIGT) under three separate conditions: without any prior exercise, and immediately after single 20-min bouts of cycle ergometer exercise at an intensity of 50% and 70% of maximal oxygen uptake (Vo(2max)). The exercise intensities were close to the lower and upper boundaries recommended by the ADA and ACSM. Results: Glucose disappearance constant (K-G), S-G(2)*, and S-I(2)* increased after exercise in an intensity-dependent manner. Increases in S-G(2)* (+237.1 +/- 50.5%), S-I(2)* (+225.6 +/- 51.9%), and K-G ( + 151.7 +/- 16.5%) following exercise at 70% Vo(2max) were statistically significant ( P < 0.05), whereas those at 50% Vo(2max) were not. Conclusions: In conclusion, a single bout of exercise acutely improves S-I(2)* and S-G(2)* in individuals with normal glucose tolerance in an intensity-dependent manner.
  • N Yahagi, H Shimano, K Hasegawa, K Ohashi, T Matsuzaka, Y Najima, M Sekiya, S Tomita, H Okazaki, Y Tamura, Y Iizuka, K Ohashi, R Nagai, S Ishibashi, T Kadowaki, M Makuuchi, S Ohnishi, J Osuga, N Yamada  EUROPEAN JOURNAL OF CANCER  41-  (9)  1316  -1322  2005/06  [Not refereed][Not invited]
     
    Hepatocellular carcinoma is a very common neoplastic disease in countries where hepatitis viruses B and/or C are prevalent. Small hepatocellular carcinoma lesions detected by ultrasonography at an early stage are often hyperechoic because they are composed of well-differentiated cancer cells that are rich in triglyceride droplets. The triglyceride content of hepatocytes depends in part on the rate of lipogenesis. Key lipogenic enzymes, such as fatty acid synthase, are co-ordinately regulated at the transcriptional level. We therefore examined the mRNA expression of lipogenic enzymes in human hepatocellular carcinoma samples from 10 patients who had undergone surgical resection. All of the samples exhibited marked elevation of expression of mRNA for lipogenic enzymes, such as fatty acid synthase, acetyl-CoA carboxylase and ATP citrate lyase, compared with surrounding non-cancerous liver tissue. In contrast, the changes in mRNA expression of SREBP-1, a transcription factor that regulates a battery of lipogenic enzymes, did not show a consistent trend. In some cases where SREBP-1 was elevated, the main contributing isoform was SREBP-1c rather than SREBP-1a. Thus, lipogenic enzymes are markedly induced in hepatocellular carcinomas, and in some cases SREBP-1c is involved in this activation. (c) 2005 Elsevier Ltd. All rights reserved.
  • High mobility group protein-B1 interacts with sterol regulatory element-binding proteins to enhance their DNA binding.
    J Biol Chem  280: 27523-27532-  2005  [Not refereed][Not invited]
  • M Sata, H Nishimatsu, J Osuga, K Tanaka, N Ishizaka, S Ishibashi, Y Hirata, R Nagai  HYPERTENSION  43-  (6)  1214  -1220  2004/06  [Not refereed][Not invited]
     
    3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.
  • N Yahagi, H Shimano, T Matsuzaka, M Sekiya, Y Najima, S Okazaki, H Okazaki, Y Tamura, Y Iizuka, N Inoue, Y Nakagawa, Y Takeuchi, K Ohashi, K Harada, T Gotoda, R Nagai, T Kadowaki, S Ishibashi, J Osuga, N Yamada  JOURNAL OF BIOLOGICAL CHEMISTRY  279-  (20)  20571  -20575  2004/05  [Not refereed][Not invited]
     
    Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.
  • M Sekiya, JI Osuga, H Okazaki, N Yahagi, K Harada, WJ Shen, Y Tamura, S Tomita, Y Iizuka, K Ohashi, M Okazaki, M Sata, R Nagai, T Fujita, H Shimano, FB Kraemer, N Yamada, S Ishibashi  JOURNAL OF BIOLOGICAL CHEMISTRY  279-  (15)  15084  -15090  2004/04  [Not refereed][Not invited]
     
    Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL-/-) by cross-breeding HSL-/- mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/ HSL-/- mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL+/+ mice. Lep(ob/ob)/ HSL-/- mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.
  • Diabetic Med  21: 136-141-  2004  [Not refereed][Not invited]
  • T Yatagai, T Nakamura, S Nagasaka, Kusaka, I, S Ishikawa, A Yoshitaka, S Ishibashi  DIABETES RESEARCH AND CLINICAL PRACTICE  63-  (1)  19  -26  2004/01  [Not refereed][Not invited]
     
    Insulin-sensitizing thiazolidinediones (TZDs) decrease inflammatory markers such as high-sensitive C-reactive protein (hsCRP) in sera in addition to their hypoglycemic effects. However, factors associated with the decrease in serum hsCRP concentrations are unclear. In the present study, an effect of troglitazone on serum hsCRP levels was investigated and compared with its effect on glycemia. A total of 34 subjects with type 2 diabetes (17 men and 17 women, aged 54 2 years and body mass index (BMI) 26.7 +/- 10.6 kg/m(2), mean +/- S.E.) were studied. Nineteen out of the 34 subjects was treated with troglitazone 400 mg daily for 12 weeks. The remaining 15 subjects were treated with metformin 750 mg daily as a control group. Baseline hsCRP levels were comparable between the two groups, and those were positively associated with fasting insulin levels. After treatment, glycemic control assessed by HbA1c and fasting glucose levels improved in both groups, whereas insulin sensitivity index estimated by homeostasis model assessment (HOMA-R) decreased only in the troglitazone-treated group. Serum levels of hsCRP significantly decreased from 916 +/- 210 ng/ml to 569 +/- 123 ng/ml (P < 0.05) in the troglitazone-treated group, whereas the levels remained unchanged in the metformin-treated group (from 1087 +/- 248 ng/ml to 1152 +/- 301 ng/ml). In the troglitazone-treated group, there was no difference in the absolute and percent change in serum hsCRP levels between responders, who displayed the decrease in HbA1c, greater than 0.6% (n = 12), and the remaining non-responders (n = 7). The decrease in serum hsCRP concentrations was negatively related to baseline levels of serum hsCRP and insulin and HOMA-R. In conclusion, troglitazone, but not metfort-nin, reduced serum hsCRP levels in type 2 diabetic patients. The decrease in serum hsCRP concentrations by troglitazone was associated with the pretreatment levels of hsCRP and insulin resistance, but independent of the changes in glycemia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
  • Thyroid  14:307-310-  2004  [Not refereed][Not invited]
  • Mol Endocrinol  18:549-557-  2004  [Not refereed][Not invited]
  • Kidney Intern  66: 1493-502-  2004  [Not refereed][Not invited]
  • T Yoshikawa, T Ide, H Shimano, N Yahagi, M Amemiya-Kudo, T Matsuzaka, S Yatoh, T Kitamine, H Okazaki, Y Tamura, M Sekiya, A Takahashi, AH Hasty, R Sato, H Sone, JI Osuga, S Ishibashi, N Yamada  MOLECULAR ENDOCRINOLOGY  17-  (7)  1240  -1254  2003/07  [Not refereed][Not invited]
     
    Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.
  • T Ide, H Shimano, T Yoshikawa, N Yahagi, M Amemiya-Kudo, T Matsuzaka, M Nakakuki, S Yatoh, Y Iizuka, S Tomita, K Ohashi, A Takahashi, H Sone, T Gotoda, JI Osuga, S Ishibashi, N Yamada  MOLECULAR ENDOCRINOLOGY  17-  (7)  1255  -1267  2003/07  [Not refereed][Not invited]
     
    Fatty acid metabolism is transcriptionally regulated by two reciprocal systems: peroxisome proliferator-activated receptor (PPAR)alpha controls fatty acid degradation, whereas sterol regulatory element-binding protein-1c activated by liver X receptor (LXR) regulates fatty acid synthesis. To explore potential interactions between LXR and PPAR, the effect of LXR activation on PPARalpha signaling was investigated. In luciferase reporter gene assays, overexpression of LXRalpha or beta suppressed PPARalpha-induced peroxisome proliferator response element-luciferase activity in a dose-dependent manner. LXR agonists, T0901317 and 22(R)hydroxycholesterol, dose dependently enhanced the suppressive effects of LXRs. Gel shift assays demonstrated that LXR reduced binding of PPARalpha/retinoid X receptor (RXR) alpha to peroxisome proliferator response element. Addition of increasing amounts of RXRalpha restored these inhibitory effects in both luciferase and gel shift assays, suggesting the presence of RXRalpha competition. In vitro protein binding assays demonstrated that activation of LXR by an LXR agonist promoted formation of LXR/RXRalpha and, more importantly, LXR/PPARalpha heterodimers, leading to a reduction of PPARalpha/RXRalpha formation. Supportively, in vivo administration of the LXR ligand to mice and rat primary hepatocytes substantially decreased hepatic mRNA levels of PPARalpha-targeted genes in both basal and PPARalpha agonist-induced conditions. The amount of nuclear PPARalpha/RXR heterodimers in the mouse livers was induced by treatment with PPARalpha ligand, and was suppressed by superimposed LXR ligand. Taken together with data from the accompanying paper (Yoshikawa, T., T. Ide, H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, S. Yatoh, T. Kitamine, H. Okazaki, Y. Tamura, M. Sekiya, A. Takahashi, A. H. Hasty, R. Sato, H. Sone, J. Osuga, S. Ishibashi, and N. Yamada, Endocrinology 144: 1240-1254) describing PPARalpha suppression of the LXR-sterol regulatory element-binding protein-1c pathway, we propose the presence of an intricate network of nutritional transcription factors with mutual interactions, resulting in efficient reciprocal regulation of lipid degradation and lipogenesis.
  • N Yahagi, H Shimano, T Matsuzaka, Y Najima, M Sekiya, Y Nakagawa, T Ide, S Tomita, H Okazaki, Y Tamura, Y Iizuka, K Ohashi, T Gotoda, R Nagai, S Kimura, S Ishibashi, J Osuga, N Yamada  JOURNAL OF BIOLOGICAL CHEMISTRY  278-  (28)  25395  -25400  2003/07  [Not refereed][Not invited]
     
    The tumor suppressor p53 is a transcription factor that activates or represses its target genes after various genotoxic stresses. We have previously shown that sterol regulatory element-binding protein-1 (SREBP-1), a key transcriptional regulator of triglyceride synthesis, and the lipogenic enzymes under its control are markedly suppressed in adipocytes from genetically obese ob/ob mice. Here we demonstrate that p53 and its target genes are highly induced in adipocytes of ob/ob mice in a fed state, leading to the negative regulation of SREBP-1 and thereby lipogenic genes. In fact, disruption of p53 in ob/ob mice completely suppressed the p53-regulated genes to wild-type levels and partially restored expression of lipogenic enzymes. Consistently, reporter gene analysis showed that p53 overexpression suppressed the promoter activity of the SREBP-1c gene and its downstream genes. Thus, the activation of p53 might constitute a negative feedback loop against excess fat accumulation in adipocytes. In conclusion, we discovered a novel role of p53 in the pathophysiology of obesity.
  • Y Tamura, H Adachi, J Osuga, K Ohashi, N Yahagi, M Sekiya, H Okazaki, S Tomita, Y Iizuka, H Shimano, R Nagai, S Kimura, M Tsujimoto, S Ishibashi  JOURNAL OF BIOLOGICAL CHEMISTRY  278-  (15)  12613  -12617  2003/04  [Not refereed][Not invited]
     
    Advanced glycation end products (AGEs) are nonenzymatically glycosylated proteins, which accumulate in vascular tissues in aging and diabetes. Receptors for AGEs include scavenger receptors, which recognize acetylated low density lipoproteins (Ac-LDL) such as scavenger receptor class AI/AII (SR-A), cell surface glycoprotein CD36, scavenger receptor class B type I (SRBI), and lectin-like oxidized low density lipoprotein receptor-1. The broad ligand repertoire of these receptors as well as the diversity of the receptors for AGEs have prompted us to examine whether AGEs are also recognized by the novel scavenger receptors, which we have recently isolated from a cDNA library prepared from human umbilical vein endothelial cells, such as the scavenger receptor expressed by endothelial cells-I (SREC-I); the fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1 (FEEL-1); and its paralogous protein, FEEL-2. At 4 degreesC, I-125-AGE-bovine serum albumin (BSA) exhibited high affinity specific binding to Chinese hamster ovary (CHO) cells overexpressing FEEL-1 (CHO-FEEL-1) and FEEL-2 (CHO-FEEL-2) with K-d of 2.55 and 1.68 mug/ml, respectively, but not to CHO cells expressing SREC (CHO-SREC) and parent CHO cells. At 37 degreesC, I-125-AGE-BSA was taken up and degraded by CHO-FEEL-1 and CHO-FEEL-2 cells but not by CHO-SREC and parent CHO cells. Thus, the ability to bind Ac-LDL is not necessarily a prerequisite to bind AGEs. The I-125-AGE-BSA binding to CHO-FEEL-1 and CHO-FEEL-2 cells was effectively inhibited by Ac-LDL and polyanionic SR-A inhibitors such as fucoidan, polyinosinic acids, and dextran sulfate but not by native LDL, oxidized LDL, or HDL. FEEL-1, which is expressed by the liver and vascular tissues, may recognize AGEs, thereby contributing to the development of diabetic vascular complications and atherosclerosis.
  • G Fujisawa, K Okada, S Muto, N Fujita, N Itabashi, E Kusano, S Ishibashi  HYPERTENSION  41-  (3)  493  -498  2003/03  [Not refereed][Not invited]
     
    Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid receptors (MRs). However, the underlying cellular mechanisms remain unclear. To determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated with only high salt after the operation. The DOCA/salt-induced perivascular collagen deposition was completely abolished by cariporide and spironolactone. DOCA/salt-induced interstitial collagen deposition was partially and completely suppressed by spironolactone and cariporide, respectively. The rats exposed to DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial regions, a finding that was completely inhibited by cariporide but not by spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly increased. This was partially and completely reversed by spironolactone and cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt-induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide completely prevents the detrimental effects of DOCA/salt on the heart. We also demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs through NHE1 activation.
  • NeuroReport  14:1997-2000-  2003  [Not refereed][Not invited]
  • Resistance to high fat diet-induced obesity associated with altered expression of adipose specific genes in hormone-sensitive lipase deficient mice.
    Am J Physiol Endocrinol Metab.  285:E1182-95-  2003  [Not refereed][Not invited]
  • J Biol Chem.  278:42936-41-  2003  [Not refereed][Not invited]
  • Effect of glimepiride on serum adiponectin level in subjects with type 2 diabetes.
    Diabetes Care  26: 2215-2216-  2003  [Not refereed][Not invited]
  • Diabetes Care  26: 1640-1641-  2003  [Not refereed][Not invited]
  • H Okazaki, JI Osuga, K Tsukamoto, N Isoo, T Kitamine, Y Tamura, S Tomita, M Sekiya, N Yahagi, Y Iizuka, K Ohashi, K Harada, T Gotoda, H Shimano, S Kimura, R Nagai, N Yamada, S Ishibashi  JOURNAL OF BIOLOGICAL CHEMISTRY  277-  (35)  31893  -31899  2002/08  [Not refereed][Not invited]
     
    Cholesterol ester (CE)-laden foam cells are a hallmark of atherosclerosis. To determine whether stimulation of the hydrolysis of cytosolic CE can be used as a novel therapeutic modality of atherosclerosis, we overexpressed hormone-sensitive lipase (HSL) in THP-1 macrophage-like cells by adenovirus-mediated gene delivery, and we examined its effects on the cellular cholesterol trafficking. We show here that the overexpression of HSL robustly increased neutral CE hydrolase activity and completely eliminated CE in the cells that had been preloaded with CE by incubation with acetylated low density lipoprotein. In these cells, cholesterol efflux was stimulated in the absence or presence of high density lipoproteins, which might be at least partially explained by the increase in the expression of ABCA1 Importantly, these effects were achieved without the addition of acyl-CoA:cholesterol acyltransferase inhibitor, cAMP, or even high density lipoproteins. Furthermore, the uptake and degradation of acetylated low density lipoprotein was significantly reduced probably by decreased expression of scavenger receptor A and CD36. Notably, the cells with stimulated CE hydrolysis did not exhibit either buildup of free cholesterol or cytotoxicity. In conclusion, increased hydrolysis of CE by the overexpression of HSL leads to complete elimination of CE from THP-1 foam cells not only by increasing efflux but also by decreasing influx of cholesterol.
  • Y Imai, T Shindo, K Maemura, M Sata, Y Saito, Y Kurihara, M Akishita, J Osuga, S Ishibashi, K Tobe, H Morita, Y Oh-hashi, T Suzuki, H Maekawa, K Kangawa, N Minamino, Y Yazaki, R Nagai, H Kurihara  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY  22-  (8)  1310  -1315  2002/08  [Not refereed][Not invited]
     
    Objective-Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). Methods and Results-Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively, P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N-w-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%. respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. Conclusions-Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.
  • N Yahagi, H Shimano, AH Hasty, T Matsuzaka, T Ide, T Yoshikawa, M Amemiya-Kudo, S Tomita, H Okazaki, Y Tamura, Y Iizuka, K Ohashi, J Osuga, K Harada, T Gotoda, R Nagai, S Ishibashi, N Yamada  JOURNAL OF BIOLOGICAL CHEMISTRY  277-  (22)  19353  -19357  2002/05  [Not refereed][Not invited]
     
    Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.
  • T Yoshikawa, H Shimano, N Yahagi, T Ide, M Amemiya-Kudo, T Matsuzaka, M Nakakuki, S Tomita, H Okazaki, Y Tamura, Y Iizuka, K Ohashi, A Takahashi, H Sone, J Osuga, T Gotoda, S Ishibashi, N Yamada  JOURNAL OF BIOLOGICAL CHEMISTRY  277-  (3)  1705  -1711  2002/01  [Not refereed][Not invited]
     
    Previous studies have demonstrated that polyunsaturated fatty acids (PUFAs) suppress sterol regulatory element-binding protein 1c (SREBP-1c) expression and, thus, lipogenesis. In the current study, the molecular mechanism for this suppressive effect was investigated with luciferase reporter gene assays using the SREBP-1c promoter in HEK293 cells. Consistent with previous data, the addition of PUFAs to the medium in the assays robustly inhibited the SREBP-1c promoter activity. Deletion and mutation of the two liver X receptor (LXR)-responsive elements (LXREs) in the SREBP-1c promoter region eliminated this suppressive effect, indicating that both LXREs are important PUFA-suppressive elements. The luciferase activities of both SREBP-1c promoter and LXRE enhancer constructs induced by co-expression of LXRalpha or -beta were strongly suppressed by the addition of various PUFAs (arachidonic acid > eicosapentaenoic acid > docosahexaenoic acid > linoleic acid), whereas saturated or mono-unsaturated fatty acids had minimal effects. Gel shift mobility and ligand binding domain activation assays demonstrated that PUFA suppression of SREBP-1c expression is mediated through its competition with LXR ligand in the activation of the ligand binding domain of LXR, thereby inhibiting binding of LXP/retinoid X receptor heterodimer to the LXREs in the SREBP-le promoter. These data suggest that PUFAs could be deeply involved in nutritional regulation of cellular fatty acid levels by inhibiting an LXR-SREBP-1c system crucial for lipogenesis.
  • Endocrine J  49:425-431-  2002  [Not refereed][Not invited]
  • The long-term effects of self-management education for patients with type 2 diabetes on glycemic control: response to Norris et al.
    Diabetes Care  25: 2115-2116-  2002  [Not refereed][Not invited]
  • Lipolysis in the absence of hormone-sensitive lipase: Evidence for common mechanism regulating distinct lipases.
    Diabetes  51:3368-3375-  2002  [Not refereed][Not invited]
  • Diabetic Med  19: 347-348-  2002  [Not refereed][Not invited]
  • P-gp-induced modulation of regulatory volume increase occurs via PKC in mouse proximal tubule.
    Am J Phisiol Renal Physiol  282:F65-76-  2002  [Not refereed][Not invited]
  • Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs.
    J Lipid Res  43: 911-920-  2002  [Not refereed][Not invited]
  • Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha
    J Lipid Res  43:107-14-  2002  [Not refereed][Not invited]
  • Nephron  91: 167-169-  2002  [Not refereed][Not invited]
  • An endocrinopathy characterized by dysfunction of the pituitary-adrenal axis and alopecia universalis: supporting the entity of a triple H syndrome.
    European J Endocrinol  147: 357-361.-  2002  [Not refereed][Not invited]
  • Differences in E2F subunit expression in quiescent and proliferating vascular smooth muscle cells.
    Am J Physiol Heart Circ Physiol.  283:H204-12-  2002  [Not refereed][Not invited]
  • Obesity is a critical risk factor for worsening of glucose tolerance in a family with the mutant insulin receptor.
    Diabetes Care  25: 1484-1485-  2002  [Not refereed][Not invited]
  • Transcriptional activities of nuclear SREBP-1a, -1c, and ミ2 to different target promoters of lipogenic and cholesterogenic genes.
    J Lipid Res  43: 1220-35-  2002  [Not refereed][Not invited]
  • S Perrey, S Ishibashi, N Yahagi, J Osuga, R Tozawa, H Yagyu, K Ohashi, T Gotoda, K Harada, Z Chen, Y Iizuka, F Shionoiri, N Yamada  METABOLISM-CLINICAL AND EXPERIMENTAL  50-  (1)  36  -40  2001/01  [Not refereed][Not invited]
     
    Thiazolidinediones (TZDs) are antidiabetic insulin-sensitizing agents that bind to peroxisome proliferator-activated receptor gamma (PPAR gamma) and have potent adipogenic effects on 3T3-L1 preadipocytes. In fully differentiated 3T3-L1 adipocytes, TZDs markedly decreased PPAR gamma mRNA levels without reducing the expression of genes that are positively regulated by PPAR gamma, such as adipocyte lipid-binding protein 2 (aP2) or lipoprotein lipase-(LPL). PPAR gamma mRNA levels were also downregulated by tumor necrosis factor alpha (TNF alpha), an antiadipogenic cytokine. We propose that the downregulation of PPAR gamma is not the common denominator of the metabolic effects of TZDs and TNF alpha on mature adipocytes, Copyright (C) 2001 by W.B. Saunders Company.
  • Atherosclerosis  154:51-60-  2001  [Not refereed][Not invited]
  • Lipoprotein(a) and atherosclerosis.
    Arterioscler Thromb Vasc Biol.  21:1-2-  2001  [Not refereed][Not invited]
  • Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.
    Arterioscler Thromb Vasc Biol  21:372-7-  2001  [Not refereed][Not invited]
  • CD36 deficiency and insulin resistance.
    Lancet  358:243-  2001  [Not refereed][Not invited]
  • Intracellular signaling mechanisms for the P-glycoprotein-induced modulation of regulatory volume increase in the mouse proximal tubule.
    Am J Physiol Renal Physiol  282:F65-F76-  2001  [Not refereed][Not invited]
  • Horm Metab Res  33:472-9-  2001  [Not refereed][Not invited]
  • Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
    J Lipid Res.  41:1199-204-  2000  [Not refereed][Not invited]
  • Intern Med  39:472-3-  2000  [Not refereed][Not invited]
  • J Biol Chem.  275:31069-77-  2000  [Not refereed][Not invited]
  • Chronic inhibitory effect of insulin on plasma lipid concentrations in rats with transplanted pancreas.
    Transplantation  69:2038-42-  2000  [Not refereed][Not invited]
  • J Biol Chem  275:31078-85-  2000  [Not refereed][Not invited]
  • Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice.
    J Lipid Res  40:1677-85-  1999  [Not refereed][Not invited]
  • J Biol Chem  274:30843-8-  1999  [Not refereed][Not invited]
  • LM Sun, S Ishibashi, J Osuga, K Harada, K Ohashi, T Gotoda, Y Fukuo, Y Yazaki, N Yamada  ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY  18-  (6)  941  -946  1998/06  [Not refereed][Not invited]
     
    To characterize the clinical features associated with the Trp(64)Arg mutation of the beta 3-adrenergic receptor (beta 3-AR), the effects of this mutation, in particular the homozygous state (Arg/Arg), on obesity, blood pressure, and plasma lipoproteins were investigated in 2 populations: subjects residing on a small isolated island (group 1; n=746) and patients residing in Tokyo who attend a clinic for metabolic diseases (group 2; n=371). The allelic frequency of the Trp(64)Arg mutation was 23.4% in group 1 and 18.3% in group 2. No significant difference in the body mass index was observed between subjects with 3 different genotypes in each group. There was a trend that the Arg/Arg had higher systolic blood pressure than the Trp/Trp in both groups, but the differences were not statistically significant. The plasma LDL cholesterol levels were significantly lower in Arg/Arg than in Trp/Trp in men from the group 1 cohort (2.82+/-0.84 versus 3.19+/-0.7 mmol/L, P<0.05). These results suggest that the homozygous Trp(64)Arg mutation is not a major contributing factor for obesity, but potentially contributed to higher systolic blood pressure and low plasma levels of LDL cholesterol in Japanese men.
  • Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice.
    Lab Invest  78:423-34-  1998  [Not refereed][Not invited]
  • Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.
    J Clin Invest  102:386-94-  1998  [Not refereed][Not invited]
  • Improved glycemic control in a diabetic patient after discontinuation of allopurinol administration.
    Diabetes Care  21:192-3-  1998  [Not refereed][Not invited]
  • A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus.
    Arterioscler Thromb Vasc Biol  18:1330-4-  1998  [Not refereed][Not invited]
  • Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.
    J Clin Invest  101:1784-8-  1998  [Not refereed][Not invited]
  • Biochem Biophys Res Commun.  236:375-8-  1997  [Not refereed][Not invited]
  • Biochem Biophys Res Commun  233:655-7-  1997  [Not refereed][Not invited]
  • Atherosclerosis  135:235-9-  1997  [Not refereed][Not invited]
  • Skipping of exon 14 and possible instability of both the mRNA and the resultant truncated protein underlie a common cholesteryl ester transfer protein deficiency in Japan.
    Arterioscler Thromb Vasc Biol  17:1376-81-  1997  [Not refereed][Not invited]
  • Sick sinus syndrome in association with malignant lymphoma.
    Eur Heart J  17:968-  1996  [Not refereed][Not invited]
  • Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy.
    Diabetes  45:507-12-  1996  [Not refereed][Not invited]
  • Transcription factor PU.1 mediates induction of c-fms in vascular smooth muscle cells: a mechanism for phenotypic change tophagocytic cells.
    Mol Cell Biol  16:2264-73-  1996  [Not refereed][Not invited]
  • Transgenic mouse and gene therapy.
    Diabetes  Suppl 3:S129-32-  1996  [Not refereed][Not invited]
  • Biochem Biophys Res Commun  211:761-6-  1995  [Not refereed][Not invited]
  • Overexpression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia.
    Arterioscler Thromb Vasc Biol  15:1688-94-  1995  [Not refereed][Not invited]
  • Biochem Biophys Res Commun  214:653-62-  1995  [Not refereed][Not invited]
  • Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic m・・・
    J Clin Invest  95:1133-9-  1995  [Not refereed][Not invited]
     
    Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells.
  • Rapid genotyping of low density lipoprotein receptor knockout mice using a polymerase chain reaction technique.
    Lab Anim  29:447-9-  1995  [Not refereed][Not invited]
  • Asialoglycoprotein receptor deficiency in mice lacking the minor receptor subunit.
    J Biol Chem  269:27803-6-  1994  [Not refereed][Not invited]
  • Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
    J Clin Invest  93:1885-93-  1994  [Not refereed][Not invited]
  • Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM.
    Diabetes Care  16:564-9-  1993  [Not refereed][Not invited]
  • Apolipoprotein E metabolism in sciatic nerves of diabetic rats. Implication for diabetic neuropathy.
    Horm Metab Res  2:82-7-  1993  [Not refereed][Not invited]
  • Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.
    J Clin Invest  92:883-93-  1993  [Not refereed][Not invited]
  • Role of monocyte colony-stimulating factor in foam cell generation.
    Proc Soc Exp Biol Med  200:240-4-  1992  [Not refereed][Not invited]
  • Characterization of monoclonal anti-rabbit apolipoprotein E antibodies and chemical composition of lipoproteins separated by anti-apolipoprotein E immuno-affinity chromatography.
    J Biochem (Tokyo)  109:204-10-  1991  [Not refereed][Not invited]
  • Oxidation-labile subfraction of human plasma low density lipoprotein isolated by ion-exchange chromatography.
    J Lipid Res  32:763-73-  1991  [Not refereed][Not invited]
  • Effects of human recombinant macrophage colony-stimulating factor on the secretion of lipoprotein lipase from macrophages.
    Arterioscler Thromb  11:1315-21-  1991  [Not refereed][Not invited]
  • The enhanced cellular uptake of very-low-density lipoprotein enriched in apolipoprotein E.
    Biochim Biophys Acta  1082:63-70-  1991  [Not refereed][Not invited]
  • Overexpression of low density lipoprotein receptor on Chinese hamster ovary cells generates foam cells.
    Arterioscler Thromb.  11:1310-4-  1991  [Not refereed][Not invited]
  • Occurrence of multiple aberrantly spliced mRNAs upon a donor splice site mutation that causes familial lipoprotein lipase deficiency.
    J Biol Chem  266:24757-62-  1991  [Not refereed][Not invited]
  • Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.
    J Clin Invest  88:1856-64-  1991  [Not refereed][Not invited]
  • Endocrinol Jpn  37:437-42-  1990  [Not refereed][Not invited]
  • Plasma cholesterol-lowering activity of monocyte colony-stimulating factor (M-CSF).
    Ann N Y Acad Sci  587:362-70-  1990  [Not refereed][Not invited]
  • Human monocyte colony-stimulating factor enhances the clearance of lipoproteins containing apolipoprotein B-100 via both low density lipoprotein receptor-dependent and -independent pathways in rabbits.
    J Biol Chem  265:12869-75-  1990  [Not refereed][Not invited]
  • Effect of exogenous apo E on the cellular binding of lipoproteins.
    Gerontology  36 Suppl 1:42-8-  1990  [Not refereed][Not invited]
  • Apolipoprotein E and lipoprotein lipase secreted from human monocyte-derived macrophages modulate very low density lipoprotein uptake.
    J Biol Chem  265:3040-7-  1990  [Not refereed][Not invited]
  • Monocyte colony-stimulating factor enhances uptake and degradation of acetylated low density lipoproteins and cholesterol esterification in human monocyte-derived macrophages.
    J Biol Chem  265:14109-17-  1990  [Not refereed][Not invited]
  • Increased clearance of plasma cholesterol after injection of apolipoprotein E into Watanabe heritable hyperlipidemic rabbits.
    Proc Natl Acad Sci U S A  86:665-9-  1989  [Not refereed][Not invited]
  • Plasma apolipoproteins in patients with multi-infarct dementia.
    Atherosclerosis  79:257-60-  1989  [Not refereed][Not invited]
  • A neonatal case of apolipoprotein C-II deficiency.
    Eur J Pediatr  148:550-2-  1989  [Not refereed][Not invited]
  • Composition of very-low-density lipoproteins in non-insulin-dependent diabetes mellitus.
    Clin Chem  35:808-12-  1989  [Not refereed][Not invited]
  • Enhanced lipoprotein lipase secretion from human monocyte-derived macrophages caused by hypertriglyceridemic very low density lipoproteins.
    Arteriosclerosis  9:650-5-  1989  [Not refereed][Not invited]
  • Down-regulation of hepatic LDL receptor protein and messenger RNA in fasted rabbits.
    J Biochem (Tokyo)  104:712-6-  1988  [Not refereed][Not invited]
  • Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells.
    J Biochem (Tokyo)  101:331-8-  1987  [Not refereed][Not invited]
  • Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells.
    J Biochem (Tokyo)  101:331-8-  1987  [Not refereed][Not invited]
  • Nippon Naika Gakkai Zasshi  76:100-5-  1987  [Not refereed][Not invited]
  • High-cholesterol diet-induced lipoproteins stimulate lipoprotein lipase secretion in cultured rat alveolar macrophages.
    Biochim Biophys Acta  922:103-10-  1987  [Not refereed][Not invited]
  • Immunohistochemical localization of apolipoprotein E in atherosclerotic lesions of the aorta and coronary arteries.
    Atherosclerosis  60:1-6-  1986  [Not refereed][Not invited]
  • Plasma apolipoprotein CII levels in hypertriglyceridemia
    Metabolism  35:781-5-  1986  [Not refereed][Not invited]
  • Lipoprotein lipase in mouse peritoneal macrophages: the effects of insulin and dexamethasone.
    J Biochem (Tokyo)  100:1373-8-  1986  [Not refereed][Not invited]
  • Hyperlipidaemia in patients with hypopituitarism.
    Acta Endocrinol (Copenh)  110:456-60-  1985  [Not refereed][Not invited]
  • A case of polymyositis associated with hypertriglyceridemia due to decline of lipoprotein lipase activity.
    Nippon Naika Gakkai Zasshi  73:368-73-  1984  [Not refereed][Not invited]

Research Grants & Projects

  • Elucidation of lipolytic mechanism and its application for the development of novel treatment for diabetes and atherosclerosis
    Date (from‐to) : 2001 -2005
  • Development of novel therapy for diabetes and atherosclerosis


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