The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases
Abstract
1. Introduction
2. Autophagy
2.1. Membrane Rearrangement of Autophagy Process
2.2. Molecular Machinery of Autophagy
3. Overview of mTOR Signaling Pathway
3.1. mTOR Structure
3.2. Molecular Composition of mTORC1 and mTORC2
3.3. Cellular Processes Downstream of mTORC1 and mTORC2
3.4. Upstream Regulation of mTORC1 and mTORC2
3.5. The Role of mTOR in Liver Metabolism and Liver Disease
4. Regulation of Autophagy by mTOR
5. Effect of Autophagy on Liver Injury by Targeting Upstream Pathway of mTOR
5.1. PI3K/AKT/mTOR/Autophagy Signaling Pathway
5.1.1. Liver Fibrosis
5.1.2. Hepatitis B Virus
5.1.3. Hepatocellular Carcinoma
5.2. AMPK/mTOR/Autophagy Signaling Pathway
5.2.1. Non-Alcoholic Fatty Liver Disease
5.2.2. Liver Ischemia and Reperfusion
5.2.3. Liver Cancer
5.3. Ras/Raf/MEK/ERK/mTOR/Autophagy Signaling Pathway
5.4. Cross-Talk in the Upstream Pathway of the mTOR-Mediated Autophagy
5.4.1. Cross-Talk between PI3K/AKT and Ras/Raf/MEK/ERK Pathways
5.4.2. Cross-Talk between PI3K/AKT and AMPK Pathways
5.4.3. Cross-Talk between AMPK and Ras/Raf/MEK/ERK Pathways
5.4.4. Cross-Talk between the Upstream Pathways of mTOR-Mediated Autophagy in Liver Injury
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Liver Disease | Signaling Pathway | Effect | Target | Reference |
---|---|---|---|---|
Liver Fibrosis | PI3K/AKT/mTOR/autophagy | IGFBPrP1 promotes the activation of HSCs by activating PI3K/AKT/mTOR-mediated autophagy. MH, Rutin and Curcumin inhibit the activation of HSCs by activating PI3K/AKT/mTOR-mediated autophagy. | Inhibition of PI3K/AKT/mTOR- mediated autophagy Over-activation of PI3K/AKT/ mTOR-mediated autophagy | [153] [154,155] |
Hepatitis B virus | PI3K/AKT/mTOR/autophagy | microRNA-99 family can promote replication of HBV by inducing PI3K/AKT/mTOR-mediated autophagy. | Inhibition of PI3K/AKT/mTOR- mediated autophagy | [157] |
Non-alcoholic fatty liver disease | AMPK/mTOR/autophagy | LRG, FNDC5 and H2S activate AMPK/mTOR-mediated autophagy improve NAFLD. Acetaminophen inhibits AMPK/mTOR-mediated autophagy aggravating fat accumulation in NAFLD. | Activation of AMPK/mTOR- mediated autophagy | [201,202] [204] [207] |
Liver ischemia and reperfusion | AMPK/mTOR/autophagy | Isoflurane activates AMPK/mTOR pathway mediated autophagy to improve hepatic ischemia-reperfusion injury. Inhibition of GSK3β can ameliorate hepatic ischemia-reperfusion injury by activating AMPK/mTOR-mediated autophagy. | Activation of AMPK/mTOR- mediated autophagy | [108] [212] |
Liver Cancer | PI3K/AKT/mTOR/autophagy AMPK/mTOR/autophagy Ras/Raf/MEK/ERK/ mTOR/autophagy | Brusatol activates PI3K/AKT/mTOR-mediated autophagy of hepatoma cells, thereby effectively inducing apoptosis of hepatoma cells, inhibiting proliferation of hepatoma cells as well as invasion and migration of tumors. Bri and BCLB over-activate AMPK/mTOR-mediated autophagy to inhibit the growth and proliferation of hepatoma cells. Glycochenodeoxycholate activates AMPK/mTOR-mediated autophagy to promote hepatocellular carcinoma invasion and migration. RA-XII inhibits AMPK/mTOR-mediated autophagy to inhibit the growth and colony formation of HepG 2 cells. Bicyclol and AZA activate Ras/Raf/MEK/ERK/ mTOR-mediated autophagy to inhibit the proliferation of HepG2 or promote their senescence. | Over-activation of PI3K/AKT/ mTOR-mediated autophagy Over-activation of AMPK/mTOR- mediated autophagy Inhibition of AMPK/mTOR- mediated autophagy Activation of Ras/Raf/MEK/ERK/ mTOR-mediated autophagy | [167] [214,215] [217] [109] [242,243] |
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Wang, H.; Liu, Y.; Wang, D.; Xu, Y.; Dong, R.; Yang, Y.; Lv, Q.; Chen, X.; Zhang, Z. The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases. Cells 2019, 8, 1597. https://doi.org/10.3390/cells8121597
Wang H, Liu Y, Wang D, Xu Y, Dong R, Yang Y, Lv Q, Chen X, Zhang Z. The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases. Cells. 2019; 8(12):1597. https://doi.org/10.3390/cells8121597
Chicago/Turabian StyleWang, Haojie, Yumei Liu, Dongmei Wang, Yaolu Xu, Ruiqi Dong, Yuxiang Yang, Qiongxia Lv, Xiaoguang Chen, and Ziqiang Zhang. 2019. "The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases" Cells 8, no. 12: 1597. https://doi.org/10.3390/cells8121597
APA StyleWang, H., Liu, Y., Wang, D., Xu, Y., Dong, R., Yang, Y., Lv, Q., Chen, X., & Zhang, Z. (2019). The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases. Cells, 8(12), 1597. https://doi.org/10.3390/cells8121597