研究者総覧

石橋 俊 (イシバシ シュン)

  • 内科学講座(内分泌代謝学部門) 教授
Last Updated :2021/09/22

研究者情報

ホームページURL

J-Global ID

研究キーワード

  • insulin   insulin   vascular biology   atherosclerosis   metabolism   glucose   lipoprotein   lipid   diabetes   

研究分野

  • ライフサイエンス / 代謝、内分泌学

経歴

  • 1994年 - 2001年  Assistant professor,
  • 2001年  - professor, Division of Endocrinology and
  • 1992年 - 1994年  Assistant instructor,
  • 1989年 - 1992年  Rearch fellow,
  • 1989年  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,

学歴

  •         - 1982年   東京大学   Faculty of Medicine   Medicine

所属学協会

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

研究活動情報

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年11月 [査読無し][通常論文]
     
    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年10月 [査読無し][通常論文]
     
    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年07月 [査読無し][通常論文]
     
    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年06月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • M Sata, H Nishimatsu, J Osuga, K Tanaka, N Ishizaka, S Ishibashi, Y Hirata, R Nagai HYPERTENSION 43 (6) 1214 -1220 2004年06月 [査読無し][通常論文]
     
    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年05月 [査読無し][通常論文]
     
    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年04月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • T Yatagai, T Nakamura, S Nagasaka, Kusaka, I, S Ishikawa, A Yoshitaka, S Ishibashi DIABETES RESEARCH AND CLINICAL PRACTICE 63 (1) 19 -26 2004年01月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • Mol Endocrinol 18:549-557 2004年 [査読無し][通常論文]
  • Kidney Intern 66: 1493-502 2004年 [査読無し][通常論文]
  • 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 Mol Endocrinol 17 (7) 1240 -1254 2003年07月 [査読無し][通常論文]
     
    Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling.
  • 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年07月 [査読無し][通常論文]
     
    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年07月 [査読無し][通常論文]
     
    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年04月 [査読無し][通常論文]
     
    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年03月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • J Biol Chem. 278:42936-41 2003年 [査読無し][通常論文]
  • Effect of glimepiride on serum adiponectin level in subjects with type 2 diabetes.
    Diabetes Care 26: 2215-2216 2003年 [査読無し][通常論文]
  • Diabetes Care 26: 1640-1641 2003年 [査読無し][通常論文]
  • 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年08月 [査読無し][通常論文]
     
    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年08月 [査読無し][通常論文]
     
    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年05月 [査読無し][通常論文]
     
    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年01月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Lipolysis in the absence of hormone-sensitive lipase: Evidence for common mechanism regulating distinct lipases.
    Diabetes 51:3368-3375 2002年 [査読無し][通常論文]
  • Diabetic Med 19: 347-348 2002年 [査読無し][通常論文]
  • P-gp-induced modulation of regulatory volume increase occurs via PKC in mouse proximal tubule.
    Am J Phisiol Renal Physiol 282:F65-76 2002年 [査読無し][通常論文]
  • Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs.
    J Lipid Res 43: 911-920 2002年 [査読無し][通常論文]
  • Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha
    J Lipid Res 43:107-14 2002年 [査読無し][通常論文]
  • Nephron 91: 167-169 2002年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Differences in E2F subunit expression in quiescent and proliferating vascular smooth muscle cells.
    Am J Physiol Heart Circ Physiol. 283:H204-12 2002年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • 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年01月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • Lipoprotein(a) and atherosclerosis.
    Arterioscler Thromb Vasc Biol. 21:1-2 2001年 [査読無し][通常論文]
  • Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.
    Arterioscler Thromb Vasc Biol 21:372-7 2001年 [査読無し][通常論文]
  • CD36 deficiency and insulin resistance.
    Lancet 358:243 2001年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Horm Metab Res 33:472-9 2001年 [査読無し][通常論文]
  • Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
    J Lipid Res. 41:1199-204 2000年 [査読無し][通常論文]
  • Intern Med 39:472-3 2000年 [査読無し][通常論文]
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  • Chronic inhibitory effect of insulin on plasma lipid concentrations in rats with transplanted pancreas.
    Transplantation 69:2038-42 2000年 [査読無し][通常論文]
  • J Biol Chem 275:31078-85 2000年 [査読無し][通常論文]
  • Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice.
    J Lipid Res 40:1677-85 1999年 [査読無し][通常論文]
  • J Biol Chem 274:30843-8 1999年 [査読無し][通常論文]
  • 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年06月 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.
    J Clin Invest 102:386-94 1998年 [査読無し][通常論文]
  • Improved glycemic control in a diabetic patient after discontinuation of allopurinol administration.
    Diabetes Care 21:192-3 1998年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.
    J Clin Invest 101:1784-8 1998年 [査読無し][通常論文]
  • Biochem Biophys Res Commun. 236:375-8 1997年 [査読無し][通常論文]
  • Biochem Biophys Res Commun 233:655-7 1997年 [査読無し][通常論文]
  • Atherosclerosis 135:235-9 1997年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Sick sinus syndrome in association with malignant lymphoma.
    Eur Heart J 17:968 1996年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Transgenic mouse and gene therapy.
    Diabetes Suppl 3:S129-32 1996年 [査読無し][通常論文]
  • Biochem Biophys Res Commun 211:761-6 1995年 [査読無し][通常論文]
  • Overexpression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia.
    Arterioscler Thromb Vasc Biol 15:1688-94 1995年 [査読無し][通常論文]
  • Biochem Biophys Res Commun 214:653-62 1995年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
     
    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年 [査読無し][通常論文]
  • Asialoglycoprotein receptor deficiency in mice lacking the minor receptor subunit.
    J Biol Chem 269:27803-6 1994年 [査読無し][通常論文]
  • Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
    J Clin Invest 93:1885-93 1994年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Apolipoprotein E metabolism in sciatic nerves of diabetic rats. Implication for diabetic neuropathy.
    Horm Metab Res 2:82-7 1993年 [査読無し][通常論文]
  • Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.
    J Clin Invest 92:883-93 1993年 [査読無し][通常論文]
  • Role of monocyte colony-stimulating factor in foam cell generation.
    Proc Soc Exp Biol Med 200:240-4 1992年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Oxidation-labile subfraction of human plasma low density lipoprotein isolated by ion-exchange chromatography.
    J Lipid Res 32:763-73 1991年 [査読無し][通常論文]
  • Effects of human recombinant macrophage colony-stimulating factor on the secretion of lipoprotein lipase from macrophages.
    Arterioscler Thromb 11:1315-21 1991年 [査読無し][通常論文]
  • The enhanced cellular uptake of very-low-density lipoprotein enriched in apolipoprotein E.
    Biochim Biophys Acta 1082:63-70 1991年 [査読無し][通常論文]
  • Overexpression of low density lipoprotein receptor on Chinese hamster ovary cells generates foam cells.
    Arterioscler Thromb. 11:1310-4 1991年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.
    J Clin Invest 88:1856-64 1991年 [査読無し][通常論文]
  • Endocrinol Jpn 37:437-42 1990年 [査読無し][通常論文]
  • Plasma cholesterol-lowering activity of monocyte colony-stimulating factor (M-CSF).
    Ann N Y Acad Sci 587:362-70 1990年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Effect of exogenous apo E on the cellular binding of lipoproteins.
    Gerontology 36 Suppl 1:42-8 1990年 [査読無し][通常論文]
  • Apolipoprotein E and lipoprotein lipase secreted from human monocyte-derived macrophages modulate very low density lipoprotein uptake.
    J Biol Chem 265:3040-7 1990年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • 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年 [査読無し][通常論文]
  • Plasma apolipoproteins in patients with multi-infarct dementia.
    Atherosclerosis 79:257-60 1989年 [査読無し][通常論文]
  • A neonatal case of apolipoprotein C-II deficiency.
    Eur J Pediatr 148:550-2 1989年 [査読無し][通常論文]
  • Composition of very-low-density lipoproteins in non-insulin-dependent diabetes mellitus.
    Clin Chem 35:808-12 1989年 [査読無し][通常論文]
  • Enhanced lipoprotein lipase secretion from human monocyte-derived macrophages caused by hypertriglyceridemic very low density lipoproteins.
    Arteriosclerosis 9:650-5 1989年 [査読無し][通常論文]
  • Down-regulation of hepatic LDL receptor protein and messenger RNA in fasted rabbits.
    J Biochem (Tokyo) 104:712-6 1988年 [査読無し][通常論文]
  • Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells.
    J Biochem (Tokyo) 101:331-8 1987年 [査読無し][通常論文]
  • Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells.
    J Biochem (Tokyo) 101:331-8 1987年 [査読無し][通常論文]
  • Nippon Naika Gakkai Zasshi 76:100-5 1987年 [査読無し][通常論文]
  • High-cholesterol diet-induced lipoproteins stimulate lipoprotein lipase secretion in cultured rat alveolar macrophages.
    Biochim Biophys Acta 922:103-10 1987年 [査読無し][通常論文]
  • Immunohistochemical localization of apolipoprotein E in atherosclerotic lesions of the aorta and coronary arteries.
    Atherosclerosis 60:1-6 1986年 [査読無し][通常論文]
  • Plasma apolipoprotein CII levels in hypertriglyceridemia
    Metabolism 35:781-5 1986年 [査読無し][通常論文]
  • Lipoprotein lipase in mouse peritoneal macrophages: the effects of insulin and dexamethasone.
    J Biochem (Tokyo) 100:1373-8 1986年 [査読無し][通常論文]
  • Hyperlipidaemia in patients with hypopituitarism.
    Acta Endocrinol (Copenh) 110:456-60 1985年 [査読無し][通常論文]
  • A case of polymyositis associated with hypertriglyceridemia due to decline of lipoprotein lipase activity.
    Nippon Naika Gakkai Zasshi 73:368-73 1984年 [査読無し][通常論文]

共同研究・競争的資金等の研究課題

  • Elucidation of lipolytic mechanism and its application for the development of novel treatment for diabetes and atherosclerosis
    研究期間 : 2001年 -2005年
  • Development of novel therapy for diabetes and atherosclerosis


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