中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 39 Issue 8
Aug.  2023
Turn off MathJax
Article Contents

The mechanism and potential of mammalian target of rapamycin complex 1(mTORC1) in treatment for nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2023.08.027
Research funding:

Liaoning Doctoral Research Start-Up Fund Project (2022-BS-140)

More Information
  • Corresponding author: ZHENG Changqing, zhengchangqing88@163.com (ORCID: 0000-0003-4782-5715)
  • Received Date: 2023-05-19
  • Accepted Date: 2023-06-20
  • Published Date: 2023-08-20
  • Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide and can progress to nonalcoholic steatohepatitis, liver cirrhosis, and liver cancer. Mammalian target of rapamycin (mTOR) is an atypical serine/threonine protein kinase and plays an important role in the processes such as cell growth, apoptosis, autophagy, and metabolism. This article elaborates on the role of the mTOR complex 1 (mTORC1) signaling pathway in cell metabolism, growth, and differentiation during in the onset of NAFLD and further proposes the value and potential of the mTORC1 pathway in the research on therapeutic drugs for NAFLD.

     

  • loading
  • [1]
    FORLANO R, SIGON G, MULLISH BH, et al. Screening for NAFLD-current knowledge and challenges[J]. Metabolites, 2023, 13(4): 536. DOI: 10.3390/metabo13040536.
    [2]
    KUMAR S, DUAN Q, WU R, et al. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis[J]. Adv Drug Deliv Rev, 2021, 176: 113869. DOI: 10.1016/j.addr.2021.113869.
    [3]
    RAZA S, RAJAK S, UPADHYAY A, et al. Current treatment paradigms and emerging therapies for NAFLD/NASH[J]. Front Biosci (Landmark Ed), 2021, 26(2): 206-237. DOI: 10.2741/4892.
    [4]
    WANG CE, XU WT, GONG J, et al. Research progress in the treatment of non-alcoholic fatty liver disease[J]. Clin J Med Offic, 2022, 50(9): 897-899, 903. DOI: 10.16680/j.1671-3826.2022.09.06.

    王彩娥, 许文涛, 宫建, 等. 非酒精性脂肪性肝病治疗研究进展[J]. 临床军医杂志, 2022, 50(9): 897-899, 903. DOI: 10.16680/j.1671-3826.2022.09.06.
    [5]
    LIU GY, SABATINI DM. mTOR at the nexus of nutrition, growth, ageing and disease[J]. Nat Rev Mol Cell Biol, 2020, 21(4): 183-203. DOI: 10.1038/s41580-019-0199-y.
    [6]
    DELEYTO-SELDAS N, EFEYAN A. The mTOR-autophagy axis and the control of metabolism[J]. Front Cell Dev Biol, 2021, 9: 655731. DOI: 10.3389/fcell.2021.655731.
    [7]
    SZWED A, KIM E, JACINTO E. Regulation and metabolic functions of mTORC1 and mTORC2[J]. Physiol Rev, 2021, 101(3): 1371-1426. DOI: 10.1152/physrev.00026.2020.
    [8]
    HAN J, WANG Y. mTORC1 signaling in hepatic lipid metabolism[J]. Protein Cell, 2018, 9(2): 145-151. DOI: 10.1007/s13238-017-0409-3.
    [9]
    MASUDA M, YOSHIDA-SHIMIZU R, MORI Y, et al. Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes[J]. J Nutr Biochem, 2022, 106: 109017. DOI: 10.1016/j.jnutbio.2022.109017.
    [10]
    KIM DH, SARBASSOV DD, ALI SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery[J]. Cell, 2002, 110(2): 163-175. DOI: 10.1016/s0092-8674(02)00808-5.
    [11]
    KOREN I, REEM E, KIMCHI A. DAP1, a novel substrate of mTOR, negatively regulates autophagy[J]. Curr Biol, 2010, 20(12): 1093-1098. DOI: 10.1016/j.cub.2010.04.041.
    [12]
    WAN W, YOU Z, XU Y, et al. mTORC1 phosphorylates acetyltransferase p300 to regulate autophagy and lipogenesis[J]. Mol Cell, 2017, 68(2): 323-335. e6. DOI: 10.1016/j.molcel.2017.09.020.
    [13]
    WU W, LI K, GUO S, et al. P300/HDAC1 regulates the acetylation/deacetylation and autophagic activities of LC3/Atg8-PE ubiquitin-like system[J]. Cell Death Discov, 2021, 7(1): 128. DOI: 10.1038/s41420-021-00513-0.
    [14]
    NNAH IC, WANG B, SAQCENA C, et al. TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy[J]. Autophagy, 2019, 15(1): 151-164. DOI: 10.1080/15548627.2018.1511504.
    [15]
    LI K, WADA S, GOSIS BS, et al. Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3[J]. PLoS Biol, 2022, 20(3): e3001594. DOI: 10.1371/journal.pbio.3001594.
    [16]
    HOSOKAWA N, HARA T, KAIZUKA T, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy[J]. Mol Biol Cell, 2009, 20(7): 1981-1991. DOI: 10.1091/mbc.e08-12-1248.
    [17]
    ALERS S, LÖFFLER AS, WESSELBORG S, et al. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks[J]. Mol Cell Biol, 2012, 32(1): 2-11. DOI: 10.1128/MCB.06159-11.
    [18]
    CHO S, LEE G, PICKERING BF, et al. mTORC1 promotes cell growth via m6A-dependent mRNA degradation[J]. Mol Cell, 2021, 81(10): 2064-2075. e8. DOI: 10.1016/j.molcel.2021.03.010.
    [19]
    UNO K, YAMADA T, ISHIGAKI Y, et al. A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals[J]. Nat Commun, 2015, 6: 7940. DOI: 10.1038/ncomms8940.
    [20]
    MUNSON MJ, ALLEN GF, TOTH R, et al. mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival[J]. EMBO J, 2015, 34(17): 2272-2290. DOI: 10.15252/embj.201590992.
    [21]
    YU X, LONG YC, SHEN HM. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy[J]. Autophagy, 2015, 11(10): 1711-1728. DOI: 10.1080/15548627.2015.1043076.
    [22]
    HUANG TJ, REN JJ, ZHANG QQ, et al. IGFBPrP1 accelerates autophagy and activation of hepatic stellate cells via mutual regulation between H19 and PI3K/AKT/mTOR pathway[J]. Biomed Pharmacother, 2019, 116: 109034. DOI: 10.1016/j.biopha.2019.109034.
    [23]
    DAN HC, BALDWIN AS. Differential involvement of IkappaB kinases alpha and beta in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt[J]. J Immunol, 2008, 180(11): 7582-7589. DOI: 10.4049/jimmunol.180.11.7582.
    [24]
    BAR-PELED L, CHANTRANUPONG L, CHERNIACK AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1[J]. Science, 2013, 340(6136): 1100-1106. DOI: 10.1126/science.1232044.
    [25]
    GOSIS BS, WADA S, THORSHEIM C, et al. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1[J]. Science, 2022, 376(6590): eabf8271. DOI: 10.1126/science.abf8271.
    [26]
    REIS-BARBOSA PH, MARCONDES-DE-CASTRO IA, MARINHO TS, et al. The mTORC1/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice[J]. Clin Res Hepatol Gastroenterol, 2022, 46(6): 101922. DOI: 10.1016/j.clinre.2022.101922.
    [27]
    SAIKIA R, JOSEPH J. AMPK: a key regulator of energy stress and calcium-induced autophagy[J]. J Mol Med (Berl), 2021, 99(11): 1539-1551. DOI: 10.1007/s00109-021-02125-8.
    [28]
    RAMIREZ REYES J, CUESTA R, PAUSE A. Folliculin: A regulator of transcription through AMPK and mTOR signaling pathways[J]. Front Cell Dev Biol, 2021, 9: 667311. DOI: 10.3389/fcell.2021.667311.
    [29]
    PAQUETTE M, YAN M, RAMÍREZ-REYES J, et al. Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways[J]. Sci Rep, 2021, 11(1): 21268. DOI: 10.1038/s41598-021-99958-7.
    [30]
    DONG R, ZHANG X, LIU Y, et al. Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease[J]. Phytomedicine, 2023, 112: 154700. DOI: 10.1016/j.phymed.2023.154700.
    [31]
    LIU R, ZHANG HB, YANG J, et al. Curcumin alleviates isoproterenol-induced cardiac hypertrophy and fibrosis through inhibition of autophagy and activation of mTOR[J]. Eur Rev Med Pharmacol Sci, 2018, 22(21): 7500-7508. DOI: 10.26355/eurrev_201811_16291.
    [32]
    MA N, WANG YK, XU S, et al. PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling[J]. Nat Commun, 2021, 12(1): 3059. DOI: 10.1038/s41467-021-23285-8.
    [33]
    PARK J, RAH SY, AN HS, et al. Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis[J]. Metabolism, 2023, 141: 155516. DOI: 10.1016/j.metabol.2023.155516.
    [34]
    LI X, GONG H, YANG S, et al. Pectic bee pollen polysaccharide from rosa rugosa alleviates diet-induced hepatic steatosis and insulin resistance via induction of AMPK/mTOR-mediated autophagy[J]. Molecules, 2017, 22(5): 699. DOI: 10.3390/molecules22050699.
    [35]
    ZHENG W, ZHOU J, SONG S, et al. Dipeptidyl-peptidase 4 inhibitor sitagliptin ameliorates hepatic insulin resistance by modulating inflammation and autophagy in ob/ob mice[J]. Int J Endocrinol, 2018, 2018: 8309723. DOI: 10.1155/2018/8309723.
    [36]
    CANG X, WANG Y, ZENG J, et al. C9orf72 knockdown alleviates hepatic insulin resistance by promoting lipophagy[J]. Biochem Biophys Res Commun, 2022, 588: 15-22. DOI: 10.1016/j.bbrc.2021.12.018.
  • 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 (243) PDF downloads(16) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return