肥胖导致STAT-1依赖性NASH和STAT-3依赖性HC
Marcus Grohmann1, Florian Wiede2, Garron T Dodd1
1Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Cell
|November 21, 2018
概括
肥胖会导致癌症,包括肝癌,因为它会产生氧化应激. 这种压力使TCTP,一种酶失活,导致非酒精性脂肪肝炎 (NASH),纤维化和HCC发展的不同途径.
科学领域:
- 肝病学
- 癌症学
- 免疫学
背景情况:
- 肥胖是各种癌症的重要危险因素,特别是肝细胞癌 (HCC).
- 肥胖,非酒精性脂肪肝炎 (NASH),纤维化,肝硬化和HCC之间的确立联系表明它们的进展顺序.
- 新出现的证据表明,在肥胖驱动的HCC中,这些疾病之间存在潜在的分离.
研究的目的:
- 研究T细胞蛋白氨酸酶 (TCPTP) 在与肥胖相关的肝病原体中的作用.
- 确定NASH和纤维化是否是肥胖中HCC发展的先决条件.
- 阐明氧化应激对NASH,纤维化和HCC的独立贡献.
主要方法:
- 使用肥胖C57BL/ 6小鼠与肝细胞特异性TCPTP删除.
- 用化学致癌物来评估独立于NASH/纤维化的HCC发展.
- 操纵了STAT-1和STAT-3的信号通道.
主要成果:
- 在肥胖小鼠中,TCPTP缺失促进了T细胞的招募,NASH,纤维化和HCC.
- 抑制STAT-1信号,减少T细胞的招募和NASH/纤维化,但没有HCC.
- 在没有影响NASH/纤维化的情况下,STAT-3信号的纠正可以预防HCC.
- 即使没有NASH/纤维化,TCPTP删除也加速了致癌物诱导的HCC.
结论:
- 肥胖引起的肝氧化应激可以独立地驱动纳氏肺炎,纤维化和HCC.
- 在该模型中,STAT-3信号传递对HCC的发展至关重要,而STAT-1则更多地参与NASH和纤维化.
- 在肥胖症中,NASH和纤维化并不是HCC发展的必需步骤.
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