Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.
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NRF2促进肝自噬有缺陷的小鼠纤维化和肿瘤发生的发展。
DOI：
10.1016/j.jhep.2014.04.043
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发表时间：
2014-09
影响因子：
25.7
通讯作者：
Ding, Wen-Xing
中科院分区：
文献类型：
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作者：
Ni, Hong-Min;Woolbright, Benjamin L.;Williams, Jessica;Copple, Bryan;Cui, Wei;Luyendyk, James P.;Jaeschke, Hartmut;Ding, Wen-Xing
自噬是一种细胞内溶酶体降解过程，在调节肝脏正常生理功能中起重要作用。本研究的目的是探讨肝脏自噬功能丧失导致肝脏炎症、纤维化和肿瘤发生的机制。通过将Atg 5 Flox/Flox小鼠与白蛋白Cre小鼠杂交产生肝细胞特异性Atg 5敲除小鼠。这些小鼠还与Nrf 2敲除小鼠杂交，以产生Atg 5 Flox/Flox，白蛋白Cre+/Nrf 2 −/−双敲除小鼠。这些小鼠被饲养长达15个月的不同时间点，并采集血液和肝脏组织进行生化和组织学分析。肝细胞特异性Atg 5缺失导致肝脏中细胞凋亡、炎症和纤维化增加。肝细胞特异性Atg 5基因敲除小鼠的细胞凋亡增加可能是由于异常多泛素化蛋白（蛋白毒性）的积累和促凋亡蛋白和抗凋亡蛋白的稳态破坏。所有这些病理变化早在1个月开始，持续12-15个月。在9-15个月大时，这些小鼠也发生肝细胞腺瘤。有趣的是，Atg 5肝脏特异性基因敲除小鼠中Nrf 2的缺失显著消除了这些病理变化，表明该转录因子在肝脏病理机制中的关键作用。我们的研究结果提供了遗传学证据，即肝细胞自噬的丧失会导致细胞死亡，从而导致肝脏炎症、纤维化和肿瘤发生。我们还证明了Nrf 2的持续激活对于肝细胞自噬缺陷小鼠中发生的肝脏炎症，纤维化和最终肿瘤发生至关重要。
Autophagy is an intracellular lysosomal degradation process that plays an important role in regulating normal physiological functions of the liver. The purpose of the present study was to investigate the mechanism(s) by which the loss of hepatic autophagy leads to liver inflammation, fibrosis and tumorigenesis. Hepatocyte-specific Atg5 knockout mice were generated by crossing Atg5 Flox/Flox mice with albumin Cre mice. These mice were also crossed with Nrf2 knockout mice to generate Atg5 Flox/Flox, Albumin Cre+/Nrf2−/− double knockout mice. These mice were housed for various time points up to 15 months, and blood and liver tissues were harvested for biochemical and histological analysis. Hepatocyte-specific deletion of Atg5 resulted in increased apoptosis, inflammation and fibrosis in the liver. Increased apoptosis in hepatocyte-specific Atg5 knockout mice was likely due to accumulation of aberrant polyubiquitinated proteins (proteotoxicity) and disruption of the homeostasis of pro-and anti-apoptotic proteins. All of these pathological changes started as early as one month and persisted for 12–15 months. At 9–15 months of age, these mice also developed hepatocellular adenomas. Interestingly, deletion of Nrf2 in Atg5 liver-specific knockout mice markedly abolished these pathological changes, indicating a key role for this transcription factor in the mechanism of hepatic pathology. Our results provide genetic evidence that loss of autophagy in hepatocytes causes cell death resulting in liver inflammation, fibrosis and tumorigenesis. We also demonstrate that persistent activation of Nrf2 is critical for liver inflammation, fibrosis and eventual tumorigenesis that occur in mice with defects in hepatocyte autophagy.
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影响因子：
4.6
作者：
Bridle, Kim R.;Popa, Claudia;Crawford, Darrell H. G.
通讯作者：
Crawford, Darrell H. G.
影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
64.5
作者：
Jin, Zhaoyu;Li, Yun;Ashkenazi, Avi
通讯作者：
Ashkenazi, Avi
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki