Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

Ni, Hong‐Min; Chao, Xiaojuan; Yang, Hua; Deng, Fengyan; Wang, Shaogui; Bai, Qingshun; Qian, Hui; Cui, Yue; Cui, Wei; Shi, Ying‐Hong; Zong, Wei‐Xing; Wang, Zhengtao; Yang, Li; Ding, Wen–Xing

doi:10.1002/hep.30770

Cited by 45 publications

(31 citation statements)

References 34 publications

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“…Although this therapy did not improve the mHAI, it led to complete survival of Atg7‐deficient mice after PHx. This is the opposite effect described in Atg5/mTOR double knockout mice 35 . These observations suggest that the pharmacological inhibition of mTOR might activate an Atg5/Atg7‐independent autophagy process, leading to better mouse survival.…”

Section: Discussionmentioning

confidence: 75%

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Römermann

Ansari

Schultz‐Moreira

et al. 2020

Liver International

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Background and aims Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. Methods We used a hepatospecific Atg7‐deficient murine model to address this question. Results We showed that the proliferation and regeneration capacity of Atg7‐deficient hepatocytes was impaired. On the one hand, Atg7‐deficient hepatocytes showed steady‐state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7‐deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7‐deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. Conclusion We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality.

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Section: Discussionmentioning

confidence: 75%

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Römermann

Ansari

Schultz‐Moreira

et al. 2020

Liver International

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“…Subsequent findings from mice with liver-specific deletion of either Atg5 or Atg7 show spontaneous liver tumors, unequivocally indicating that autophagy is a bona fide tumor suppressor [196,197]. Multiple mechanisms have been identified that may contribute to the autophagy deficiency-induced liver tumorigenesis, including p62-mediated noncanonical Nrf2 activation, activation of Yap and mTOR, as well as the release the DAMP molecule HMGB1 [197][198][199][200][201]. Autophagy removes damaged proteins and organelles to protect cells from the intracellular oxidative and genotoxic stress, which prevents tumor initiation [202,203].…”

Section: Mitophagy In Liver Cancermentioning

confidence: 99%

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

144

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The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.

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“…However, the protein expression level of phospho-c-Jun and total-c-Jun were comparable between the two genotypes ( Supplementary Figure S7B ). The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, the mitogen-activated protein kinase(MAPK)/ERK signaling pathway, and the Janus activated kinase/Signal Transducer and Activator of Transcription Family or transcription factors (JAK/STAT3) signaling pathway, all have been associated with cell growth 30–33 . However, we did not detect significant differences in the activation of these pathways between Atg7-/- mice and Atg7-/-/Hmgb1-/- mice ( Supplementary Figure S7C-E ).…”

Section: Resultsmentioning

confidence: 99%

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Khambu

Hong

Liu

et al. 2019

Preprint

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AbstractAutophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not known. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1) that is released from autophagy-deficient hepatocytes. However, the mechanism by which HMGB1 promotes hepatic tumorigenesis is not understood. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis using liver-specific autophagy-deficient (Atg7-/-) and Atg7-/-/Hmgb1-/- mice. We found that in Atg7-/- mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of HMGB1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. In addition, we found that expression of RAGE was only on ductual cells and Kupffer’s cells but not on hepatoctyes, which suggested that HMGB1 might promote hepatic tumor growth through a paracrine mode that altered the tumor microenvironment. Furthermore, HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potential key role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.

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Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

Cited by 45 publications

References 34 publications

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Absence of Atg7 in the liver disturbed hepatic regeneration after liver injury

Role and Mechanisms of Mitophagy in Liver Diseases

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

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