中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 39 Issue 7
Jul.  2023
Turn off MathJax
Article Contents

Mechanism of action of lipotoxicity in nonalcoholic steatohepatitis

DOI: 10.3969/j.issn.1001-5256.2023.07.024
Research funding:

National Natural Science Foundation of China (82104655)

More Information
  • Corresponding author: WANG Dong, wangdong@cdutcm.edu.cn (ORCID: 0000-0002-6387-9169)
  • Received Date: 2022-10-22
  • Accepted Date: 2022-11-29
  • Published Date: 2023-07-20
  • Nonalcoholic steatohepatitis (NASH) is an important part of the exacerbation of nonalcoholic fatty liver disease (NAFLD), and inflammation and liver damage are important pathological features of this stage. As one of the pathogenic mechanisms of NASH, lipotoxicity can regulate liver inflammation and hepatocyte apoptosis through multiple pathways. Therefore, this article elaborates on the specific regulatory mechanism of lipotoxicity on NASH from the two aspects of inflammation and hepatocyte apoptosis, which involves a variety of liver nonparenchymal cells and various signaling pathways such as JNK, NF-κB, and caspase-mediated cell apoptosis, so as to provide new ideas for the diagnosis and treatment of NASH in clinical practice.

     

  • loading
  • [1]
    POVSIC M, WONG OY, PERRY R, et al. A structured literature review of the epidemiology and disease burden of non-alcoholic steatohepatitis (NASH)[J]. Adv Ther, 2019, 36(7): 1574-1594. DOI: 10.1007/s12325-019-00960-3.
    [2]
    YOUNOSSI ZM, STEPANOVA M, RAFIQ N, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease[J]. Hepatol Commun, 2017, 1(5): 421-428. DOI: 10.1002/hep4.1054.
    [3]
    TILG H, ADOLPH TE, MOSCHEN AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: revisited after a decade[J]. Hepatology, 2021, 73(2): 833-842. DOI: 10.1002/hep.31518.
    [4]
    MARRA F, SVEGLIATI-BARONI G. Lipotoxicity and the gut-liver axis in NASH pathogenesis[J]. J Hepatol, 2018, 68(2): 280-295. DOI: 10.1016/j.jhep.2017.11.014.
    [5]
    RUI L. Energy metabolism in the liver[J]. Compr Physiol, 2014, 4(1): 177-197. DOI: 10.1002/cphy.c130024.
    [6]
    YAMAGUCHI K, YANG L, MCCALL S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis[J]. Hepatology, 2007, 45(6): 1366-1374. DOI: 10.1002/hep.21655.
    [7]
    IOANNOU GN. The role of cholesterol in the pathogenesis of NASH[J]. Trends Endocrinol Metab, 2016, 27(2): 84-95. DOI: 10.1016/j.tem.2015.11.008.
    [8]
    NEUSCHWANDER-TETRI BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites[J]. Hepatology, 2010, 52(2): 774-788. DOI: 10.1002/hep.23719.
    [9]
    WANG YJ, BIAN Y, LUO J, et al. Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation[J]. Nat Cell Biol, 2017, 19(7): 808-819. DOI: 10.1038/ncb3551.
    [10]
    GAN LT, van ROOYEN DM, KOINA ME, et al. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent[J]. J Hepatol, 2014, 61(6): 1376-1384. DOI: 10.1016/j.jhep.2014.07.024.
    [11]
    HORN CL, MORALES AL, SAVARD C, et al. Role of cholesterol-associated steatohepatitis in the development of NASH[J]. Hepatol Commun, 2022, 6(1): 12-35. DOI: 10.1002/hep4.1801.
    [12]
    LIPKE K, KUBIS-KUBIAK A, PIWOWAR A. Molecular mechanism of lipotoxicity as an interesting aspect in the development of pathological states-current view of knowledge[J]. Cells, 2022, 11(5): 844. DOI: 10.3390/cells11050844.
    [13]
    LEAMY AK, EGNATCHIK RA, YOUNG JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease[J]. Prog Lipid Res, 2013, 52(1): 165-174. DOI: 10.1016/j.plipres.2012.10.004.
    [14]
    PAGADALA M, KASUMOV T, MCCULLOUGH AJ, et al. Role of ceramides in nonalcoholic fatty liver disease[J]. Trends Endocrinol Metab, 2012, 23(8): 365-371. DOI: 10.1016/j.tem.2012.04.005.
    [15]
    SIMON J, OURO A, ALA-IBANIBO L, et al. Sphingolipids in non-alcoholic fatty liver disease and hepatocellular carcinoma: ceramide turnover[J]. Int J Mol Sci, 2019, 21(1): 40. DOI: 10.3390/ijms21010040.
    [16]
    KOYAMA Y, BRENNER DA. Liver inflammation and fibrosis[J]. J Clin Invest, 2017, 127(1): 55-64. DOI: 10.1172/JCI88881.
    [17]
    SCHUSTER S, CABRERA D, ARRESE M, et al. Triggering and resolution of inflammation in NASH[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(6): 349-364. DOI: 10.1038/s41575-018-0009-6.
    [18]
    LEROUX A, FERRERE G, GODIE V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis[J]. J Hepatol, 2012, 57(1): 141-149. DOI: 10.1016/j.jhep.2012.02.028.
    [19]
    WENFENG Z, YAKUN W, DI M, et al. Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease[J]. Ann Hepatol, 2014, 13(5): 489-495.
    [20]
    KHOMICH O, IVANOV AV, BARTOSCH B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis[J]. Cells, 2019, 9(1): 24. DOI: 10.3390/cells9010024.
    [21]
    BOUREBABA N, MARYCZ K. Hepatic stellate cells role in the course of metabolic disorders development-A molecular overview[J]. Pharmacol Res, 2021, 170: 105739. DOI: 10.1016/j.phrs.2021.105739.
    [22]
    MIYAO M, KOTANI H, ISHIDA T, et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression[J]. Lab Invest, 2015, 95(10): 1130-1144. DOI: 10.1038/labinvest.2015.95.
    [23]
    MATSUMOTO M, ZHANG J, ZHANG X, et al. The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease[J]. Free Radic Biol Med, 2018, 115: 412-420. DOI: 10.1016/j.freeradbiomed.2017.12.019.
    [24]
    NASIRI-ANSARI N, ANDROUTSAKOS T, FLESSA CM, et al. Endothelial cell dysfunction and nonalcoholic fatty liver disease (NAFLD): A concise review[J]. Cells, 2022, 11(16): 2511. DOI: 10.3390/cells11162511.
    [25]
    GENG Y, FABER KN, de MEIJER VE, et al. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?[J]. Hepatol Int, 2021, 15(1): 21-35. DOI: 10.1007/s12072-020-10121-2.
    [26]
    HIRSOVA P, GORES GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis[J]. Cell Mol Gastroenterol Hepatol, 2015, 1(1): 17-27. DOI: 10.1016/j.jcmgh.2014.11.005.
    [27]
    MUSSO G, CASSADER M, PASCHETTA E, et al. Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis[J]. Gastroenterology, 2018, 155(2): 282-302. e8. DOI: 10.1053/j.gastro.2018.06.031.
    [28]
    HETZ C, ZHANG K, KAUFMAN RJ. Mechanisms, regulation and functions of the unfolded protein response[J]. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438. DOI: 10.1038/s41580-020-0250-z.
    [29]
    MOTA M, BANINI BA, CAZANAVE SC, et al. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease[J]. Metabolism, 2016, 65(8): 1049-1061. DOI: 10.1016/j.metabol.2016.02.014.
    [30]
    SVEGLIATI-BARONI G, PIERANTONELLI I, TORQUATO P, et al. Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease[J]. Free Radic Biol Med, 2019, 144: 293-309. DOI: 10.1016/j.freeradbiomed.2019.05.029.
    [31]
    HAUCK AK, BERNLOHR DA. Oxidative stress and lipotoxicity[J]. J Lipid Res, 2016, 57(11): 1976-1986. DOI: 10.1194/jlr.R066597.
    [32]
    XIAO M, ZHONG H, XIA L, et al. Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria[J]. Free Radic Biol Med, 2017, 111: 316-327. DOI: 10.1016/j.freeradbiomed.2017.04.363.
    [33]
    SABIO G, DAVIS RJ. TNF and MAP kinase signalling pathways[J]. Semin Immunol, 2014, 26(3): 237-245. DOI: 10.1016/j.smim.2014.02.009.
    [34]
    YANG YM, KIM SY, SEKI E. Inflammation and liver cancer: molecular mechanisms and therapeutic targets[J]. Semin Liver Dis, 2019, 39(1): 26-42. DOI: 10.1055/s-0038-1676806.
    [35]
    CAZANAVE SC, MOTT JL, BRONK SF, et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis[J]. J Biol Chem, 2011, 286(45): 39336-39348. DOI: 10.1074/jbc.M111.280420.
    [36]
    MALHI H, GUICCIARDI ME, GORES GJ. Hepatocyte death: a clear and present danger[J]. Physiol Rev, 2010, 90(3): 1165-1194. DOI: 10.1152/physrev.00061.2009.
    [37]
    AKAZAWA Y, NAKAO K. To die or not to die: death signaling in nonalcoholic fatty liver disease[J]. J Gastroenterol, 2018, 53(8): 893-906. DOI: 10.1007/s00535-018-1451-5.
    [38]
    WANDRER F, LIEBIG S, MARHENKE S, et al. TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice[J]. Cell Death Dis, 2020, 11(3): 212. DOI: 10.1038/s41419-020-2411-6.
  • 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 (223) PDF downloads(32) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return