ROLE OF PPARα HUMAN HEPATIC STELLATE CELL AND HEPATOMA CELL

PPARα 人肝星状细胞和肝癌细胞的作用

• 批准号: 12670534
• 负责人: UENO Takato
• 金额: $ 2.11万
• 依托单位: KURUME UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670534/
• 关键词: HEPATIC STELLATE CELL; HEPATOMA CELL; PPAR α ACTIVATOR; COX2; IL-1; DEDIFFERENTIATION; LIPOMICS; HEPATITIS C VIRUS; PPARα; フェノフィブレート; HCV-Core蛋白; transgenic mouse; 肝発癌; 肝細胞脂肪変性; PPARγ; 脂肪肝; 肝細胞癌; フィノフィブレート

The transfection activity of cyclooxgenase-2 (COX2) is suppressed because peroxisome proliferator-activalor receptor (PPAR α) activator regulates the signal of NF-kappa B. Moreover, in well-differentiated hepatocellular carcinoma (HCC), COX2 participate in dedifferentiation. This study examined whether PPARα activator would suppress the activation of human hepatic stellate cells (HSC) and the differentiation of HCC.1) In the HSC line LI-90, and the hepatoma cell lines Huh-7, HLE, HepG2 and Hep3B, although the expressions of PPAR α and γ were detected, the expression of PPAR α was weaker than that of PPAR γ. In addition, the expression of PPAR α up-regulated by the IL-1 addition was decreased with PPAR α activator treatment.2) After the reporter plasmid which united the luciferase gene with the COX2 promoter or the NF-kappa B responsive element was transferred into LI-90, although the activation of COX2 promoter or NF-kappa B responsive element increased by IL-1 addition, it was suppressed by PPAR α activator treatment.This year we were scheduled to examine the dedifferentiation suppression effect of PPAR α activator in vitro using the hepatoma cell lines. However, since the establishment of an in vivo experiment system in which hepatitis C virus core protein transgenic mice can be treated with the direct fenofibrate (PPAR α activator), the following experiments are now progressing.1) Changes of lipids in the mice are analyzed using lipomics, which makes it possible to analyze hundreds of kinds of lipid components.2)The ultrastructural observation of liver tissues is being carried out.3) Changes of factors related to the cell cycle of hepatic cells are examined using the Western method etc.These findings from these studies are bang analyzed, and the relationship between hepatitis C virus and the lipid denaturation in hepatic cells is presently under examination.

过氧化物酶体增殖物激活物受体（PPAR α）激活剂调节NF-κ B B信号，从而抑制COX-2的转染活性。此外，在高分化肝细胞癌（HCC）中，COX 2参与去分化。本研究探讨了过氧化物酶体增殖物激活体α（PPARα）激活剂是否能抑制人肝星状细胞（HSC）的活化和肝癌的分化。1）在HSC株LI-90和肝癌细胞株Huh-7、HLE、HepG 2和Hep 3B中，虽然检测到了过氧化物酶体增殖物激活体α（PPAR α）和过氧化物酶体增殖物激活体γ（PPAR γ）的表达，但PPAR α的表达弱于PPAR γ。2）将荧光素酶基因与COX 2启动子或NF-κ B反应元件连接的报告质粒转入LI-90细胞后，虽然IL-1的加入增加了COX 2启动子或NF-κ B反应元件的激活，今年我们计划使用肝癌细胞系在体外检测PPAR α激活剂的去分化抑制作用。然而，自从建立了丙型肝炎病毒核心蛋白转基因小鼠可以直接用非诺贝特治疗的体内实验系统以来，（PPAR α激活剂），以下实验现在正在进行中。1）使用脂质组学分析小鼠中脂质的变化，这使得分析数百种脂质成分成为可能。2）正在进行肝组织的超微结构观察。3）使用Western方法等检测与肝细胞的细胞周期相关的因子的变化。对这些研究结果进行分析，目前正在检测丙型肝炎病毒与肝细胞中脂质变性之间的关系。

项目成果

Masaharu Sakamoto et al.: "Estrogen upregulates nitric oxide synthase expression in cultured rat hepatic sinusoidal endothelial cells"Journal of Hepatology. 34. 858-864 (2001)

Masaharu Sakamoto 等人：“雌激素上调培养的大鼠肝窦内皮细胞中一氧化氮合酶的表达”肝脏病学杂志。

Osamu Hashimoto, Takato Ueno, Ohtsubo Motoaki, Rina Kimura, Toru Nakamura, Hironori Koga, Takuji Torimura, Sanae Uchida, Katsumi Yamashita, Michio Sate: "TGF β 1 inhibits proteasome-dependent degradation of Wee1 and promotes G2 arrest in the retinoblastom

Osamu Hashimoto、Takato Ueno、Ohtsubo Motoaki、Rina Kimura、Toru Nakamura、Hironori Koga、Takuji Torimura、Sanae Uchida、Katsumi Yamashita、Michio Sate：“TGF β 1 抑制 Wee1 的蛋白酶体依赖性降解并促进视网膜母细胞瘤中的 G2 停滞

Takamasa Oono et al.: "Organ-specific autoimmunity in mice whose T cell repertoire is shared by a single antigenic peptide"Journal of Clinical Investigation. 108・11. 1589-1596 (2001)

Takamasa Oono 等人：“T 细胞库由单一抗原肽共享的小鼠中的器官特异性自身免疫”临床研究杂志 108・11（2001）。

Takato Ueno et al.: "Fenofibrate treatment in patients with primary biliary cirrhosis"American Journal of Gastroenterology. 97・8. 2147-2149 (2002)

Takato Ueno 等：“原发性胆汁性肝硬化患者的非诺贝特治疗”美国胃肠病学杂志 97・8 2147-2149 (2002)。

Takato Ueno: "Extracellular Matrix and the Liver"ACADEMIC PRESS. 467 (2003)

Takato Ueno：“细胞外基质和肝脏”学术出版社。