Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy.
Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy.
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DOI：
10.1016/j.jhep.2021.10.014
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发表时间：
2022-03
影响因子：
25.7
通讯作者：
Ding WX
中科院分区：
文献类型：
--
作者：
Chao X;Wang S;Fulte S;Ma X;Ahamed F;Cui W;Liu Z;Rülicke T;Zatloukal K;Zong WX;Liu W;Ni HM;Ding WX
由于 Tsc1（结节性硬化症复合物 1）缺失而导致的 mTORC1 激活或由于 Atg5 缺失而导致的肝自噬缺陷会导致小鼠自发性肝脏肿瘤发生。本研究的目的是探讨自噬如何影响 mTORC1 激活介导的肝脏代谢变化和肿瘤发生的机制。 Atg5 Flox/Flox (Atg5F/F) 和 Tsc1F/F 小鼠与白蛋白 Cre 小鼠杂交，产生肝脏特异性 Atg5 敲除 (L-Atg5 KO)、L-Tsc1 KO 和 L-Atg5/Tsc1 双 KO (DKO) 小鼠。这些小鼠与 p62/Sqstm1 F/F (p62) 和全身 Nrf2 KO 小鼠杂交，产生 L-Atg5/Tsc1/p62 和 L-Atg5/Tsc1、Nrf2 三重 KO (TKO) 小鼠。这些小鼠被饲养不同时间点长达12个月，收集血液和肝脏组织用于生化和组织学分析。L-Tsc1 KO小鼠中Atg5的缺失抑制了肝脏肿瘤的发生，但L-Tsc1 KO小鼠的死亡率增加，伴随着肝管反应（DR）、肝细胞变性和代谢重编程的急剧增强。 p62的缺失逆转了DR、肝细胞变性和代谢重编程以及L-Atg5/Tsc1 DKO小鼠的死亡率，但意外地通过激活一组致癌信号通路促进了肝脏肿瘤的发生。 Nrf2 消除显着改善了 DR，增加了肝细胞数量，并改善了 L-Atg5/Tsc1 DKO 小鼠的代谢重编程和存活率，且没有形成肿瘤。在部分人类肝细胞癌中还发现 p62 减少和 mTOR 活性增加。这些结果揭示了肝脏 p62 在抑制肿瘤发生、调节肝细胞重新增殖和由于持续 mTORC1 激活和缺陷自噬而导致的代谢重编程方面的先前未描述的功能。代谢性肝病和病毒性肝炎是常见的慢性肝病和肝细胞癌的危险因素，通常与肝自噬受损和 mTOR 激活增加有关。使用多只肝自噬缺陷且 mTOR 持续激活的基因工程小鼠，我们剖析了 mTOR、自噬、p62 和 Nrf2 之间对肝细胞再增殖、代谢重编程和肝肿瘤发生中氧化还原稳态的复杂相互作用。我们的结果揭示了 p62/Sqstm1 通过调节肝脏肿瘤发生中的肝细胞再增殖、导管反应和代谢重编程而具有意想不到的新型肿瘤抑制功能。
Either activation of mTORC1 due to loss of Tsc1 (Tuberous Sclerosis Complex 1) or defective hepatic autophagy due to loss of Atg5 leads to spontaneous liver tumorigenesis in mice. The purpose of this study was to investigate the mechanisms of how autophagy impacts mTORC1 activation-mediated liver metabolic changes and tumorigenesis. Atg5 Flox/Flox (Atg5F/F) and Tsc1F/F mice were crossed with albumin Cre mice to generate liver-specific Atg5 knockout (L-Atg5 KO), L-Tsc1 KO and L-Atg5/Tsc1 double KO (DKO) mice. These mice were crossed with p62/Sqstm1 F/F (p62) and whole body Nrf2 KO mice to generate L-Atg5/Tsc1/p62 and L-Atg5/Tsc1, Nrf2 triple KO (TKO) mice. These mice were housed for various time points up to 12 months, and blood and liver tissues were harvested for biochemical and histological analysis Deletion of Atg5 in L-Tsc1 KO mice inhibited liver tumorigenesis, but increased mortality of L-Tsc1 KO mice accompanied by drastically enhanced hepatic ductular reaction (DR), hepatocyte degeneration and metabolic reprogramming. Deletion of p62 reversed DR, hepatocyte degeneration and metabolic reprogramming as well as the mortality of L-Atg5/Tsc1 DKO mice, but unexpectedly promoted liver tumorigenesis via activation of a group of oncogenic signaling pathways. Nrf2 ablation markedly improved DR with increased hepatocyte population and improved metabolic reprogramming and survival of the L- Atg5/Tsc1 DKO mice without tumor formation. Decreased p62 and increased mTOR activity was also found in a subset of human hepatocellular carcinoma. These results reveal previously undescribed functions of hepatic p62 in suppressing tumorigenesis and regulating liver cell repopulation and metabolic reprogramming resulting from persistent mTORC1 activation and defective autophagy. Metabolic liver disease and viral hepatitis are common chronic liver diseases and risk factors of hepatocellular carcinoma, which are often associated with impaired hepatic autophagy with increased mTOR activation. Using multiple genetic engineered mice that are defective of hepatic autophagy with persistent mTOR activation, we dissected the complex interplay among mTOR, autophagy, p62 and Nrf2 on liver cell repopulation, metabolic reprogramming and redox homeostasis in liver tumorigenesis. Our results uncovered an unexpected novel tumor suppressor function of p62/Sqstm1 by regulating liver cell repopulation, ductular reaction and metabolic reprogramming in liver tumorigenesis.
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影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
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
NRF2促进肝自噬有缺陷的小鼠纤维化和肿瘤发生的发展。
影响因子：
25.7
作者：
Ni, Hong-Min;Woolbright, Benjamin L.;Williams, Jessica;Copple, Bryan;Cui, Wei;Luyendyk, James P.;Jaeschke, Hartmut;Ding, Wen-Xing
通讯作者：
Ding, Wen-Xing
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
P62/SQSTM1与维生素D受体结合抑制肝星细胞活性，纤维化和肝癌。
影响因子：
50.3
作者：
Duran A;Hernandez ED;Reina-Campos M;Castilla EA;Subramaniam S;Raghunandan S;Roberts LR;Kisseleva T;Karin M;Diaz-Meco MT;Moscat J
通讯作者：
Moscat J