Volume 44 Issue 7
Jul.  2023
Turn off MathJax
Article Contents
Chenchen LIANG, Jianpeng GAO. MSCs Promote Autophagy to Alleviate Liver Injury in NASH by Regulating AMPK/mTOR Axis[J]. Journal of Kunming Medical University, 2023, 44(7): 162-167. doi: 10.12259/j.issn.2095-610X.S20230728
Citation: Chenchen LIANG, Jianpeng GAO. MSCs Promote Autophagy to Alleviate Liver Injury in NASH by Regulating AMPK/mTOR Axis[J]. Journal of Kunming Medical University, 2023, 44(7): 162-167. doi: 10.12259/j.issn.2095-610X.S20230728

MSCs Promote Autophagy to Alleviate Liver Injury in NASH by Regulating AMPK/mTOR Axis

doi: 10.12259/j.issn.2095-610X.S20230728
  • Received Date: 2023-05-16
    Available Online: 2023-08-08
  • Publish Date: 2023-07-25
  • NASH is the characteristic pathological manifestation of the liver in MAFLD, which is a key turning point in the development of MAFLD from a relatively benign and reversible stage to liver injury and even cirrhosis and hepatocellular carcinoma. Recent studies have shown that lipid deposition and oxidative stress run through MAFLD metabolic diseases, and improving hepatic lipid deposition and oxidative stress is the main intervention approach for the treatment and prevention of NASH disease. In general, promoting autophagy levels can reduce triglyceride (TG) accumulation and oxidative stress (OS) and promote hepatocyte survival, while blocking autophagy levels may accelerate the progression of NASH. However, the activation of autophagy levels is closely related to the activation of upstream signals AMPK/mTOR/ULK1 and the regulation of EI24. EI24, an essential autophagy protein closely related to the activation of AMPK and mTOR protein channels, can accelerate the activation of autophagy flow by promoting the degradation process of autophagy-lysosome. Meanwhile, mesenchymal stem cells (MSCs) as ideal autophagy inducers have been widely studied for their excellent therapeutic effects in treating various inflammatory diseases such as NAFLD through the activation of AMPK/mTOR-mediated autophagy. Therefore, “drug-acting” mesenchymal stem cells should be used to regulate the activation of autophagy level of EI24/AMPK/mTOR to promote autophagy, inhibit adipogenesis and reduce lipid deposition, and effectively alleviate or reverse NASH liver injury, to provide a basis for elucidating the pathogenesis of NASH related diseases and developing new therapeutic strategies.
  • loading
  • [1]
    唐振霆,施晓雷. 间充质干细胞治疗非酒精性脂肪性肝炎的机制及进展[J]. 肝胆胰外科杂志,2019,31(8):504-508,513. doi: 10.11952/j.issn.1007-1954.2019.08.016
    [2]
    Wong M C S,Huang J L W,George J,et al. The changing epidemiology of liver diseases in the Asia-Pacific region[J]. Gastroenterol Hepatol,2019,16(1):57-73. doi: 10.1038/s41575-018-0055-0
    [3]
    Eslam M,Sanyal A J,George J. International consensus panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology,2020,158(7):1999-2014. doi: 10.1053/j.gastro.2019.11.312
    [4]
    Li J,Zou B,Yeo Y H,et al. Prevalence,incidence,and outcome of non-alcoholic fatty liver disease in Asia,1999-2019: A systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol,2019,4(5):389-398. doi: 10.1016/S2468-1253(19)30039-1
    [5]
    Powell E E,Wong V W,Rinella M. Non-alcoholic fatty liver disease[J]. Lancet,2021,397(10290):2212-2224. doi: 10.1016/S0140-6736(20)32511-3
    [6]
    Komatsu M. Liver autophagy: Physiology and pathology[J]. Biochem,2012,152(1):5-15. doi: 10.1093/jb/mvs059
    [7]
    Ost A,Svensson K,Ruishalme I,et al. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes[J]. Mol Med,2010,16(7-8):235-246. doi: 10.2119/molmed.2010.00023
    [8]
    Xie F,Jia L,Lin M,et al. ASPP2 attenuates triglycerides to protect against hepatocyte injury by reducing autophagy in a cell and mouse model of non-alcoholic fatty liver disease[J]. Cell Mol Med,2015,19(1):155-164. doi: 10.1111/jcmm.12364
    [9]
    Kitade H,Chen G,Ni Y,et al. Nonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatments[J]. Nutrients,2017,9(4):387. doi: 10.3390/nu9040387
    [10]
    Li F,Guo D,Zhi S,et al. Etoposide-induced protein 2.4 ameliorates high glucose-induced epithelial-mesenchymal transition by activating adenosine monophosphate-activated protein kinase pathway in renal tubular cells[J]. Int Biochem Cell Biol,2022,142(4):106-117. doi: 10.1016/j.biocel.2021.106117
    [11]
    Zhou X,Fouda S,Zeng X Y,et al. Characterization of the therapeutic profile of albiflorin for the metabolic syndrome[J]. Front Pharmacol,2019,10(2):11-51. doi: 10.3389/fphar.2019.01151
    [12]
    Ebrahim N,Ahmed I A,Hussien N I,et al. Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway[J]. Cells,2018,7(12):226. doi: 10.3390/cells7120226
    [13]
    Martin S and S Louise. Consequences of stress in these cretory pathway: The ER stress response and its role in the metabolic syndrome. Methods in molecular biology[J]. Clifton,2010,6(4):4-8. doi: 10.1007/978-1-60761-756-3_3
    [14]
    Gai R. Resveratrol ameliorates diet-induced dysregulation of lipid metabolism in zebra fish[J]. PloSone,2017,12(7):231-251. doi: 10.1371/journal.pone.0180865
    [15]
    Miura S,Suzuki A. Induction of steatohepatitis and liver tumorigenesis by enforced snail expression in hepatocytes[J]. Pathol,2020,190(6):1271-1283. doi: 10.1016/j.ajpath.2020.02.005
    [16]
    Arab H H,Al-Shorbagy M Y,Saad M A. Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: Targeting AMPK/mTOR,HMGB1/RAGE and Nrf2/HO-1 pathways[J]. Chem Biol Interact,2021,335:109-368. doi: 10.1016/j.cbi.2021.109368
    [17]
    Bu H,Liu D,Zhang G,et al. AMPK/mTOR/ULK1 Axis-Mediated pathway participates in apoptosis and autophagy induction by oridonin in colon cancer DLD-1 cells[J]. Onco Targets Ther,2020,13(4):8533-8545. doi: 10.2147/OTT.S262022
    [18]
    Wang H,Liu Y,Wang D,et al. The upstream pathway of mTOR-Mediated autophagy in liver diseases[J]. Cells,2019,8(12):1597. doi: 10.3390/cells8121597
    [19]
    张子婷,叶卓淼,陈永欣. AMPK信号通路在非酒精性脂肪肝病中的研究进展[J]. 南京医科大学学报,2019,39(8):1252-1256.
    [20]
    许银丰,汪倩,钱楚莹,等. mTORC1信号通路调控细胞自噬的研究进展[J]. 中国科学与生命科学,2022,52(2):266-272.
    [21]
    Zachari M,Ganley I G. The mammalian ULK1 complex and autophagy initiation[J]. Essays Biochem,2017,61(6):585-596. doi: 10.1042/EBC20170021
    [22]
    Xiao Y. Identification of matrine as a promising novel drug for hepatic steatosis and glucosein tolerance with HSP72 as an upstream target[J]. Britishjournalofpharmacology,2015,172(17):650-672. doi: 10.1111/bph.13209
    [23]
    Li Y. Termination of autophagy and reformation of lysosomes regulated by mTOR[J]. Nature,2010,465(7300):451-459. doi: 10.1038/nature09076
    [24]
    Valerie S. Fructose leads to hepatic steatosis inzebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition[J]. Hepatology,2014,60(5):637-641. doi: 10.1002/hep.27284
    [25]
    Li J,Fan Y,Zhang Y,et al. Resveratrol induces autophagy and apoptosis in non-small-cell lung cancer cells by activating the NGFR-AMPK-mTOR pathway[J]. Nutrients,2022,14(12):2413-2416. doi: 10.3390/nu14122413
    [26]
    荆西民,岳静静,吴卫东,等. 有氧运动对非酒精性脂肪肝大鼠肝组织AMPK蛋白活性的影响[J]. 中国运动医学杂志,2015,34(7):653-657.
    [27]
    Tian Y,Ma J,Wang W,et al. Resveratrol supplement in-hibited the NF-κB inflammation pathway through activat-ing AMPKα-SIRT1 pathway in mice with fatty liver[J]. Mol Cell Biochem,2016,422(12):75-84. doi: 10.1007/s11010-016-2807-x
    [28]
    Yuan L,Liu Q,Wang Z,Hou J,Xu P. EI24 tethers endoplasmic reticulum and mitochondria to regulate autophagy flux[J]. Cell Mol Life Sci,2020,77(8):1591-1606. doi: 10.1007/s00018-019-03236-9
    [29]
    Devkota S,Sung Y H,Choi J M,et al. Ei24-deficiency attenuates protein kinase Cα signaling and skin carcinogenesis in mice[J]. Biochem Cell Biol,2012,44(11):1887-96. doi: 10.1016/j.biocel.2012.06.034
    [30]
    Hwang M,Jun D W,Kang E H,et al. EI24,as a Component of Autophagy,is involved in pancreatic cell proliferation[J]. Front Oncol,2019,9(4):6-52. doi: 10.3389/fonc.2019.00652
    [31]
    Zhang X,Mao Y,Peng W,et al. Autophagy-related protein EI24 delays the development of pulmonary fibrosis by promoting autophagy[J]. Life Sci,2021,264(4):118664. doi: 10.1016/j.lfs.2020.118664
    [32]
    Zhao Y G,Zhao H,Miao L,et al. The p53-induced gene Ei24 is an essential component of the basal autophagy pathway[J]. Biol Chem,2012,287(50):53-63. doi: 10.1074/jbc.M112.415968
    [33]
    Filomeni G,De Z D,Cecconi F. Oxidative stress and autophagy: The clash between damage and metabolic needs[J]. Cell Death Differ,2015,22(3):377-388. doi: 10.3390/ijms21020474
    [34]
    Mao Y,Zhang X,Peng W,et al. EI24 alleviates renal interstitial fibrosis through inhibition of epithelial-mesenchymal transition and fibroblast activation[J]. FASEB,2021,35(1):221-239. doi: 10.1096/fj.202002089R
    [35]
    张小欢. EI24调控AMPK/mTOR通路促进细胞自噬减轻小鼠肺纤维化的作用及机制研究[D]. 贵阳: 贵州医科大学, 2021.
    [36]
    Amiri F,Molaei S,Bahadori M,et al. Autophagy-Modulated human bone marrow-derived mesenchymal stem cells accelerate liver restoration in mouse models of acute liver failure[J]. Iran Biomed,2016,20(3):135-144. doi: 10.7508/ibj.2016.03.002
    [37]
    张高飞,王迪,李佳美,等. 间充质干细胞通过调控自噬促进创面愈合[J]. 中国组织工程研究,2022,26(25):4058-4063. doi: 10.12307/2022.414
    [38]
    Centeno C,Markle J,Dodson E,et al. Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy[J]. Transl Med,2017,15(1):19-27. doi: 10.1186/s12967-017-1300-y
    [39]
    Yang R,Wang J,Chen X,et al. Epidermal stem cells in wound healing and regeneration.[J]. Stem Cells Int,2020,20(20):14-19. doi: 10.1155/2020/9148310
    [40]
    Oh E J,Lee H W,Kalimuthu S,et al. In vivo migration of mesenchymal stem cells to burn injury sites and their therapeutic effects in a living mouse model[J]. Control Release,2018,27(9):79-88. doi: 10.1016/j.jconrel.2018.04.020
    [41]
    Ceccariglia S,Cargnoni A,Silini A R,et al. Autophagy: A potential key contributor to the therapeutic action of mesenchymal stem cells[J]. Autophagy,2020,16(1):28-37. doi: 10.1080/15548627.2019.1630223
    [42]
    Saleh F,Itani L,Calugi S,et al. Adipose-derived mesenchymal stem cells in the treatment of obesity: A systematic review of longitudinal studies on preclinical evidence[J]. Curr Stem Cell Res Ther,2018,13(6):466-475. doi: 10.2174/1574888X13666180515160008
    [43]
    El B H,Demerdash Z,Kamel M,et al. Transplant of hepatocytes,undifferentiated mesenchymal stem cells,and in vitro hepatocyte-differentiated mesenchymal stem cells in a chronic liver failure experimental model: A comparative study[J]. Exp Clin Transplant,2018,16(1):81-89. doi: 10.6002/ect.2016.0226
    [44]
    Zare H,Jamshidi S,Dehghan M M,et al. Bone marrow or adipose tissue mesenchymal stem cells: Comparison of the therapeutic potentials in mice model of acute liver failure[J]. Cell Biochem,2018,119(7):5834-5842. doi: 10.1002/jcb.26772
    [45]
    Xie J,Liu B,Chen J,et al. Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway[J]. Biochem Biophys Res Commun,2018,495(1):546-552. doi: 10.1016/j.bbrc.2017.11.072
    [46]
    Gan L,Shen H,Li X,et al. Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma[J]. Oncol Rep,2021,45(1):107-118. doi: 10.3892/or.2020.7838
    [47]
    He H,Zeng Q,Huang G,et al. Bone marrow mesenchymal stem cell transplantation exerts neuroprotective effects following cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt pathway[J]. Brain Res,2019,1707(9):124-132. doi: 10.1016/j.brainres.2018.11.018
    [48]
    Wang B,Jia H,Zhang B,et al. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy[J]. Stem Cell Res Ther,2017,8(1):75. doi: 10.1186/s13287-016-0463-4
    [49]
    Zhu H X,Gao J L,Zhao M M,et al. Effects of bone marrow-derived mesenchymal stem cells on the autophagic activity of alveolar macrophages in a rat model of silicosis[J]. Exp Ther Med,2016,11(6):2577-2582. doi: 10.3892/etm.2016.3200
    [50]
    Liu L,Jin X,Hu CF,et al. Exosomes derived from mesenchymal stem cells rescue myocardial Ischaemia/ Reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways[J]. Cell Physiol Biochem,2017,43(1):52-68. doi: 10.1159/000480317
    [51]
    Wang X,Wang S,Zhou Y,et al. BM-MSCs protect against liver ischemia/reperfusion injury via HO-1 mediated autophagy[J]. Mol Med Rep,2018,18(2):2253-2262. doi: 10.3892/mmr.2018.9207
    [52]
    华天桢,马雨诗,房贺. 干细胞在肝损伤治疗中的应用与机制[J]. 实用医学杂志,2021,37(7):839-844.
    [53]
    Hua T,Yang M,Song H,et al. Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis[J]. Nanobiotechnology,2022,20(1):3-24. doi: 10.1186/s12951-022-01522-6
    [54]
    Tian J,Kou X,Wang R,et al. Autophagy controls mesenchymal stem cell therapy in psychological stress colitis mice[J]. Autophagy,2021,17(9):2586-2603. doi: 10.1080/15548627.2020.1821547
    [55]
    Zhao Y,Guo C,Zeng L,et al. Mesenchymal stem cells ameliorate fibrosis by enhancing autophagy via inhibiting galectin-3/Akt/mTOR pathway and by alleviating the EMT via inhibiting galectin-3/Akt/GSK3β/Snail pathway in NRK-52E fibrosis[J]. Stem Cells,2023,16(1):52-65. doi: 10.15283/ijsc22014
  • Relative Articles

    [1] Yuanyuan LI, Yaxian SONG, Yushan XU, Xiaofu ZENG, Hui YUAN, Zhao XU, Yan JIANG. The Association of Intestinal Flora Metabolite TMAO with Non-alcoholic Fatty Liver Disease. Journal of Kunming Medical University, 2024, 45(2): 77-84.  doi: 10.12259/j.issn.2095-610X.S20240210
    [2] Hang CHEN, Qi CUI, Minshan HUANG, Jianjun LIU, Lanqing MA. Research Progress of miRNA in Non-alcoholic Fatty Liver Disease. Journal of Kunming Medical University, 2024, 45(1): 1-7.  doi: 10.12259/j.issn.2095-610X.S20240101
    [3] Xuemin ZHANG, Yunfen TIAN. Role of Abnormal Bile Acid Metabolism in the Development of Non-alcoholic Fatty Liver Disease. Journal of Kunming Medical University, 2023, 44(11): 164-169.  doi: 10.12259/j.issn.2095-610X.S20231125
    [4] Lu LI, Yunfen TIAN. Research Progress on Intestinal Microflora and Non-alcoholic Fatty Liver Disease in Children. Journal of Kunming Medical University, 2023, 44(7): 148-155.  doi: 10.12259/j.issn.2095-610X.S20230708
    [5] Changyong WU, Rui WANG, Suli BAO, Ruijie LI, Huang SUN, Yujia YE, Fei XU, Yunzhu PENG. Effects of Exercise Rehabilitation on Cardiac Fibrosis and Function in Rats with Myocardial Infarction. Journal of Kunming Medical University, 2023, 44(10): 26-32.  doi: 10.12259/j.issn.2095-610X.S20231004
    [6] Shiyuan YANG, Hao ZHANG, Tuqiang HU. Effect of Pristimerin on Proliferation of Oral Squamous Cell Carcinoma CAL-27 by Regulating Autophagy. Journal of Kunming Medical University, 2023, 44(10): 92-99.  doi: 10.12259/j.issn.2095-610X.S20231024
    [7] Yixuan CHEN, Lin WANG, Xiuhong XIA, Zaikun PENG, Yi DING, Runjiao SHI, Xuefen LEI. Research Progress on the Mechanisms of Autophagy in Hepatocellular Carcinoma. Journal of Kunming Medical University, 2023, 44(4): 159-164.  doi: 10.12259/j.issn.2095-610X.S20230416
    [8] Xuesha ZHANG, Jie ZHOU, Cailin LI, Dingyu WU, Fang PENG. Effects of Periplaneta americana Extract on Autophagy and Invasive Metastasis of Subcutaneous Transplanted Hepatocellular Carcinoma in Nude Mice. Journal of Kunming Medical University, 2023, 44(10): 39-46.  doi: 10.12259/j.issn.2095-610X.S20231018
    [9] Shi CHEN, Shi FU, Zhiyong TAN, Jiansong WANG, Haifeng WANG. Research Progress of Autophagy in the Development and Treatment of Bladder Cancer. Journal of Kunming Medical University, 2023, 44(5): 168-174.  doi: 10.12259/j.issn.2095-610X.S20230503
    [10] Ziwei ZHANG, Jialin ZHENG, Xiaoyu XU, Hong WANG. Metformin Inhibits high Glucose-induced Vascular Smooth Muscle Cells Proliferation by Promoting Autophagy via AMPK/PPAR-γ. Journal of Kunming Medical University, 2023, 44(10): 60-66.  doi: 10.12259/j.issn.2095-610X.S20231026
    [11] Yongrui YANG, Liyuan WANG, Haiwen LI, Zhirong ZHAO, Rui PU, Guishuai WU, Shude LI. Scutellarin Ameliorates Liver Fibrosis in Nonalcoholic Fatty Liver Disease by Inhibiting NOX Expression. Journal of Kunming Medical University, 2022, 43(7): 38-45.  doi: 10.12259/j.issn.2095-610X.S20220721
    [12] Zihan WANG, Gaiying YE, Tao ZHAO, Jun ZHANG, Yu HU. Experimental Study on the Expression of mTOR in TMJOA Condylar Cartilage of SD Rats. Journal of Kunming Medical University, 2022, 43(10): 10-15.  doi: 10.12259/j.issn.2095-610X.S20221033
    [13] Yong-fang XU, Na WU, Yue-xin HU, Yong-mei ZHAO, Shao-ding ZHENG, Ling WEI, Si-jia ZHENG, Jian-jun LIU. Therapeutic Effect of GW7647 on Non-alcoholic Fatty Liver Disease in Rats. Journal of Kunming Medical University, 2021, 42(8): 17-22.  doi: 10.12259/j.issn.2095-610X.S20210804
    [14] Yong-jun LIU, Yin WANG, Mei YANG, E-gao YIN, Ting LI, Zhao-xing DONG. The Effect of Hydrogen-Regulated Autophagy on Pulmonary Fibrosis in Paraquat Poisoned Rats. Journal of Kunming Medical University, 2021, 42(9): 1-6.  doi: 10.12259/j.issn.2095-610X.S20210918
    [15] Ping-yan XUE, Yan JIANG, Yu-shan XU, Hui YUAN, Xuan LI, Ya-xian SONG, Hua LIU. Changes of Intestinal Flora in Non-alcoholic Fatty Liver Disease. Journal of Kunming Medical University, 2020, 41(11): 62-67.  doi: 10.12259/j.issn.2095-610X.S20201120
    [16] Shen Bao Yu , Yang Gen Meng , Li Yuan Yuan , Liu Liu , Huang Jian , Zeng Xiao Feng , Li Li Hua . . Journal of Kunming Medical University, 2020, 41(01): 163-167.
    [17] Zhu Wei Mei , Hua Peng , Luo Yu Chao , Yang Hong Ling , Li Ya Shan , Zhao Hong Yu . . Journal of Kunming Medical University, 2019, 40(02): 23-29.
    [18] Li Jing , Lei Wen , Deng Shu Hao , Fan Du , Pu Ling , Yang Dong Mei , Zhao Xiao Yuan , Li Yang , Dong Zhao Xing . . Journal of Kunming Medical University, 2019, 40(01): 10-13.
    [19] Ye Qiu Wen , Zou Tian Ning , Li Cheng Cheng , Song Ting Ting , Tan Jing . . Journal of Kunming Medical University, 2018, 39(12): 28-32.
    [20] Jiang Yan . . Journal of Kunming Medical University,
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (2575) PDF downloads(19) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return