脂毒性在非酒精性脂肪性肝炎中的作用机制

郅果果; 穆杰; 邵冰杰; 王东

doi:10.3969/j.issn.1001-5256.2023.07.024

脂毒性在非酒精性脂肪性肝炎中的作用机制

DOI: 10.3969/j.issn.1001-5256.2023.07.024

成都中医药大学基础医学院，成都 611137

基金项目:

国家自然科学基金 (82104655)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：郅果果负责撰写论文；穆杰、邵冰杰负责查阅，归纳文献；王东负责指导撰写，修改论文。

详细信息

通信作者:
王东，wangdong@cdutcm.edu.cn (ORCID: 0000-0002-6387-9169)

计量
- 文章访问数: 343
- HTML全文浏览量: 385
- PDF下载量: 55
- 被引次数: 0
出版历程
- 收稿日期: 2022-10-22
- 录用日期: 2022-11-29
- 出版日期: 2023-07-20

Mechanism of action of lipotoxicity in nonalcoholic steatohepatitis

School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

Research funding:

National Natural Science Foundation of China (82104655)

More Information

Corresponding author: WANG Dong, wangdong@cdutcm.edu.cn (ORCID: 0000-0002-6387-9169)

摘要

摘要: 非酒精性脂肪性肝炎(NASH)作为非酒精性脂肪性肝病(NAFLD)病情加剧的重要环节, 炎症和肝损伤是该阶段的重要病理学特征。脂毒性作为NASH的致病机制之一, 能够通过多种途径调控肝脏的炎症和肝细胞凋亡。本文从炎症和肝细胞凋亡两个层面重点阐述脂毒性对NASH的具体调控机制, 其中涉及了多种肝脏非实质细胞和JNK、NF-κB、caspase介导的细胞凋亡等信号通路, 为临床NASH的诊断和治疗提供了新思路。
- 非酒精性脂肪肝炎 /
- 脂毒性 /
- 炎症 /
- 细胞凋亡
Abstract: 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.
- Nonalcoholic Steatohepatitis /
- Lipotoxicity /
- Inflammation /
- Apoptosis

HTML全文

参考文献(38)

[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.