Investigation of pathophysiology and therapeutic strategies for metabolic syndrome-related steatohepatitis

代谢综合征相关脂肪性肝炎的病理生理学和治疗策略研究

基本信息

  • 批准号:
    15390235
  • 负责人:
  • 金额:
    $ 9.54万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2003
  • 资助国家:
    日本
  • 起止时间:
    2003 至 2005
  • 项目状态:
    已结题

项目摘要

Obesity and insulin resistance are the risk factors for progression hepatic fibrosis in various kinds of chronic liver diseases including alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and chronic hepatitis C. It is hypothesized that a variety of adipokines plays a pivotal role in regulation of inflammation and fibrogenesis in fatty liver diseases. We and others have demonstrated that leptin attenuates hepatic inflammation caused by endotoxin. Further, leptin enhances profibrogenic responses in the liver through up-regulation of TGF-β in sinusoidal endothelial cells and Kupffer cells. Moreover, leptin directly enhances proliferation and matrix generation, and prevents apoptosis in isolated hepatic stellate cells (HSCs). Leptin prevents apoptosis of isolated HSCs caused by gliotoxin. This anti-apoptotic effect of leptin is abolished in cells isolated from Zucker (fa/fa) rats, which lack functional leptin receptors (ObR). In regular HSCs, leptin increases phosphorylation o … More f Akt, and LY295002 reverses the inhibitory effect of leptin on caspase 3 activation caused by gliotoxin. Taken tothether, it is postulated that the PI3K-Akt pathway downstream of ObR is important in anti-apoptotic effect of leptin in HSCs. To further evaluate the role of adipokines in NASH, we utilized KK-Ay mice, which demonstrate marked obesity and type-2 diabetes. These mice spontaneously developed mild steatohepatitis with regular diet ; however, they developed severe steatohepatitis with early progression of hepatic fibrosis when they were fed a methionine-, and choline-deficient (MCD) diet. Interestingly, KK-Ay mice not only showed low serum adiponectin levels before dietary treatments, but also lacked induction of adiponectin following dietary treatments, suggesting that adiponectin play a key role in prevention of hepatic inflammation and fibrogenesis in the setting of steatohepatitis. Collectively, these findings indicated that leptin and adiponectin are profoundly involved in the pathogenesis of steatohepatitis through actions on hepatic sinusoidal cells. Less
肥胖和胰岛素抵抗是酒精性肝病、非酒精性脂肪性肝炎(NASH)和慢性丙型肝炎等多种慢性肝病肝纤维化进展的危险因素,多种脂肪因子在脂肪肝炎症和纤维化发生的调控中起关键作用。我们和其他人已经证明瘦素可以减轻内毒素引起的肝脏炎症。此外,瘦素通过上调肝窦内皮细胞和库普弗细胞中TGF-β的表达,增强肝纤维化反应。此外,瘦素还能直接促进离体肝星状细胞(hsc)的增殖和基质生成,并阻止其凋亡。瘦素可阻止胶质毒素引起的离体造血干细胞凋亡。从缺乏功能性瘦素受体(ObR)的Zucker (fa/fa)大鼠分离的细胞中,瘦素的这种抗凋亡作用被取消。在正常的hsc中,瘦素增加了Akt的磷酸化,LY295002逆转了瘦素对胶质毒素引起的caspase 3活化的抑制作用。综上所述,我们推测ObR下游的PI3K-Akt通路在瘦素在hsc中的抗凋亡作用中起重要作用。为了进一步评估脂肪因子在NASH中的作用,我们使用了KK-Ay小鼠,这些小鼠表现出明显的肥胖和2型糖尿病。这些小鼠在正常饮食的情况下自发患上轻度脂肪性肝炎;然而,当他们被喂食蛋氨酸和胆碱缺乏(MCD)饮食时,他们患上了严重的脂肪性肝炎,并伴有肝纤维化的早期进展。有趣的是,KK-Ay小鼠不仅在饮食治疗前表现出低血清脂联素水平,而且在饮食治疗后也缺乏脂联素的诱导,这表明脂联素在预防脂肪性肝炎的肝脏炎症和纤维化中发挥了关键作用。综上所述,这些发现表明瘦素和脂联素通过作用于肝窦细胞而深入参与脂肪性肝炎的发病过程。少

项目成果

期刊论文数量(22)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enomoto N, Takei Y, Hirose M, Kitamura T, Ikejima K, Sato N.: "Protective effect of thalidomide on endotoxin-induced liver injury."Alcohol Clin.Exp.Res.. 27. 2S-6S (2003)
Enomoto N、Takei Y、Hirose M、Kitamura T、Ikejima K、Sato N.:“沙利度胺对内毒素诱导的肝损伤的保护作用。”Alcohol Clin.Exp.Res.. 27. 2S-6S (2003)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Targeted gene delivery to sinusoidal endothelial cells: DNA nanoassociate bearing hyaluronan‐glycocalyx
  • DOI:
    10.1096/fj.03-0494fje
  • 发表时间:
    2004-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Takei;A. Maruyama;A. Ferdous;Y. Nishimura;S. Kawano;K. Ikejima;Shigetoshi Okumura;S. Asayama;M. Nogawa;M. Hashimoto;Y. Makino;Masahiko Kinoshita;Sumio Watanabe;T. Akaike;J. Lemasters;N. Sato
  • 通讯作者:
    Y. Takei;A. Maruyama;A. Ferdous;Y. Nishimura;S. Kawano;K. Ikejima;Shigetoshi Okumura;S. Asayama;M. Nogawa;M. Hashimoto;Y. Makino;Masahiko Kinoshita;Sumio Watanabe;T. Akaike;J. Lemasters;N. Sato
Thalidomide prevents alcoholic liver injury in rats through inhibition of Kupffer cell sensitization.
沙利度胺通过抑制库普弗细胞致敏来预防大鼠酒精性肝损伤。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Enomoto N;Takei Y;Hirose M;Ikejima K;Kitamura T;Sato N.
  • 通讯作者:
    Sato N.
Tsune I, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Takei Y, Sato N.: "Dietary glycine prevents chemical-induced experimental colitis in the rat."Gastroenterology. 125. 585-775 (2003)
Tsune I、Ikejima K、Hirose M、Yoshikawa M、Enomoto N、Takei Y、Sato N.:“膳食甘氨酸可预防大鼠化学诱发的实验性结肠炎。”胃肠病学。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor
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SATO Nobuhiro其他文献

Structuring the Effects of Functional Recovery Care in a Private Home with Care Services for Older People
通过为老年人提供护理服务,构建私人住宅功能恢复护理的效果
  • DOI:
    10.14391/ajhs.19.1
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    FUJIO Yuko;NISHIBE Makoto;ARAKI Erika;SHIMADA Hiromi;SUGIYAMA Tomoko;SATO Nobuhiro
  • 通讯作者:
    SATO Nobuhiro

SATO Nobuhiro的其他文献

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{{ truncateString('SATO Nobuhiro', 18)}}的其他基金

The "Shohin"as a Domain of No Genre:A Comprehensive Study of its Dynamics and Cultural History
作为无流派领域的“书品”:其动态与文化史的综合研究
  • 批准号:
    20520153
  • 财政年份:
    2008
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A Multidisciplinary Study of the Origins and Development of 'Table Talk' in Modern Japan
现代日本“餐桌谈话”起源与发展的多学科研究
  • 批准号:
    15520122
  • 财政年份:
    2003
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analysis of the mechanisms for cytotoxic effects in the perforin/granzyme B system
穿孔素/颗粒酶B系统细胞毒作用机制分析
  • 批准号:
    14571221
  • 财政年份:
    2002
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Innate immune response to gut-derived bacterial toxins in gastrointestinal andhepatic disorders
胃肠道和肝脏疾病中对肠源性细菌毒素的先天免疫反应
  • 批准号:
    12470129
  • 财政年份:
    2000
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
The analysis of physical stimulation to proliferative gastric cells.
物理刺激对胃细胞增殖的分析。
  • 批准号:
    08457175
  • 财政年份:
    1996
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular and cell biological investigation about the healing mechanism of gastric mucosal damage.
胃粘膜损伤愈合机制的分子和细胞生物学研究。
  • 批准号:
    06454266
  • 财政年份:
    1994
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Developmental Research on Preservation of Liver Graft by Improving the Hepatic Microcirculation
改善肝脏微循环保肝的进展研究
  • 批准号:
    03454231
  • 财政年份:
    1991
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Development of an Endoscopic System for Treating cancerous lesions by Immunological - and medico - technological Modification of Tissue Microcirculation.
开发通过免疫学和医学技术改变组织微循环来治疗癌性病变的内窥镜系统。
  • 批准号:
    02557035
  • 财政年份:
    1990
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research (B)
Disturbed Oxygen Metabolism Induced by Perturbation of Microcirculation.
微循环扰动引起的氧代谢紊乱。
  • 批准号:
    01480226
  • 财政年份:
    1989
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Dynamic Analysis of Hepatic Microcirculation and Hepatic Function by In vivo-Fluorescence Microscopy -Application to the Study of Pathogenesis and Treatment of Liver Diseases.
活体荧光显微镜动态分析肝脏微循环和肝功能-在肝病发病机制和治疗研究中的应用。
  • 批准号:
    62480195
  • 财政年份:
    1987
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)

相似海外基金

Elucidating the Role and Regulation of Proteostasis in Hepatic Fibrogenesis
阐明蛋白质稳态在肝纤维形成中的作用和调节
  • 批准号:
    10718882
  • 财政年份:
    2023
  • 资助金额:
    $ 9.54万
  • 项目类别:
Dissecting the Acid Ceramidase Pathway in Hepatic Fibrogenesis
剖析肝纤维形成中的酸性神经酰胺酶途径
  • 批准号:
    10736680
  • 财政年份:
    2023
  • 资助金额:
    $ 9.54万
  • 项目类别:
Ceramide, AMPK, and YAP/TAZ Signaling in Hepatic Fibrogenesis
肝纤维形成中的神经酰胺、AMPK 和 YAP/TAZ 信号转导
  • 批准号:
    10352024
  • 财政年份:
    2022
  • 资助金额:
    $ 9.54万
  • 项目类别:
Ceramide, AMPK, and YAP/TAZ Signaling in Hepatic Fibrogenesis
肝纤维形成中的神经酰胺、AMPK 和 YAP/TAZ 信号转导
  • 批准号:
    10544748
  • 财政年份:
    2022
  • 资助金额:
    $ 9.54万
  • 项目类别:
Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis
VLDL 分泌受损、肝纤维化进展和逆转
  • 批准号:
    9978062
  • 财政年份:
    2019
  • 资助金额:
    $ 9.54万
  • 项目类别:
Molecular MR Imaging of Hepatic Fibrogenesis
肝纤维化的分子磁共振成像
  • 批准号:
    10408068
  • 财政年份:
    2019
  • 资助金额:
    $ 9.54万
  • 项目类别:
Molecular MR Imaging of Hepatic Fibrogenesis
肝纤维化的分子磁共振成像
  • 批准号:
    10360979
  • 财政年份:
    2019
  • 资助金额:
    $ 9.54万
  • 项目类别:
Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis
VLDL 分泌受损、肝纤维化进展和逆转
  • 批准号:
    10396531
  • 财政年份:
    2019
  • 资助金额:
    $ 9.54万
  • 项目类别:
Translational studies of the induction and functional role of Th2 polarized CD4+ T-cells in chronic liver damage and hepatic fibrogenesis
Th2 极化 CD4 T 细胞在慢性肝损伤和肝纤维形成中的诱导和功能作用的转化研究
  • 批准号:
    313701256
  • 财政年份:
    2016
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Research Grants
Cellular cross-talk between liver progenitor cells and hepatic stellate cells is required for hepatic fibrogenesis
肝祖细胞和肝星状细胞之间的细胞串扰是肝纤维发生所必需的
  • 批准号:
    nhmrc : 1087125
  • 财政年份:
    2015
  • 资助金额:
    $ 9.54万
  • 项目类别:
    Project Grants
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