非酒精性脂肪肝病的发病机制与临床治疗研究进展

doi:10.3760/cma.j.cn441417-20250423-20012

摘要/Abstract

摘要：

非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）是一种慢性肝病，其发病机制与胰岛素抵抗、脂质代谢失衡及细胞应激反应等紧密关联，是一种与全身代谢紊乱相关的复杂疾病。NAFLD已成为全球慢性肝病的首要病因，临床仍缺乏特异性治疗手段。本文系统综述了NAFLD的核心病理机制与临床治疗进展，以期为深入理解NAFLD的病理生理过程、开发新的诊断和治疗策略提供理论依据。

关键词:

非酒精性脂肪肝病, 发病机制, 临床治疗, 进展

Abstract:

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease. Its pathogenesis is closely associated with insulin resistance, lipid metabolism imbalance, and cellular stress responses. It is a complex disease linked to systemic metabolic disorders. NAFLD has become the leading cause of chronic liver disease worldwide, without specific therapeutic measures. This article systematically reviews the core pathological mechanisms and clinical treatment advancements of NAFLD, so as to provide a theoretical basis for understanding the pathophysiological processes of NAFLD and the development of new diagnostic and therapeutic strategies.

Key words:

Non-alcoholic fatty liver disease, Pathogenesis, Clinical treatment, Progress

刘梦凡张凌云.

非酒精性脂肪肝病的发病机制与临床治疗研究进展 [J]. 国际医药卫生导报, 2025, 31(20): 3402-3406.

Liu Mengfan, Zhang Lingyun.

Research progress on pathogenesis and clinical treatment of non-alcoholic fatty liver disease [J]. International Medicine and Health Guidance News, 2025, 31(20): 3402-3406.

参考文献

[1] Rong L, Zou J, Ran W, et al. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD)[J]. Front Endocrinol (Lausanne), 2023,13:1087260. DOI: 10.3389/fendo.2022.1087260.
[2] Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications[J]. Gut, 2020, 69(9):1691-1705. DOI: 10.1136/gutjnl-2020-320622.
[3] Badmus OO, Hillhouse SA, Anderson CD, et al. Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways[J]. Clin Sci (Lond), 2022, 136(18):1347-1366. DOI: 10.1042/CS20220572.
[4] Scorletti E, Carr RM. A new perspective on NAFLD: focusing on lipid droplets[J]. J Hepatol, 2022, 76(4):934-945. DOI: 10.1016/j.jhep.2021.11.009.
[5] Heeren J, Scheja L. Metabolic-associated fatty liver disease and lipoprotein metabolism[J]. Mol Metab, 2021, 50:101238. DOI: 10.1016/j.molmet.2021.101238.
[6] Ebrahimi M, Seyedi SA, Nabipoorashrafi SA, et al. Lipid accumulation product (LAP) index for the diagnosis of nonalcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis[J]. Lipids Health Dis, 2023, 22(1):41. DOI: 10.1186/s12944-023-01802-6.
[7] Berk PD, Verna EC. Nonalcoholic fatty liver disease: lipids and insulin resistance[J]. Clin Liver Dis, 2016, 20(2):245-262. DOI: 10.1016/j.cld.2015.10.007.
[8] Zhang R, Zhang K. A unified model for regulating lipoprotein lipase activity[J]. Trends Endocrinol Metab, 2024, 35(6):490-504. DOI: 10.1016/j.tem.2024.02.016.
[9] Henderson GC. Plasma free fatty acid concentration as a modifiable risk factor for metabolic disease[J]. Nutrients, 2021, 13(8):2590. DOI: 10.3390/nu13082590.
[10] McGlinchey AJ, Govaere O, Geng D, et al. Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease[J]. JHEP Rep, 2022, 4(5):100477. DOI: 10.1016/j.jhepr.2022.100477.
[11] Yao Z, Gong Y, Chen W, et al. Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice[J]. Nat Metab, 2023, 5(10):1706-1725. DOI: 10.1038/s42255-023-00896-7.
[12] Yuan Y, Xu J, Jiang Q, et al. Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis[J]. J Exp Clin Cancer Res, 2024, 43(1):133. DOI: 10.1186/s13046-024-03047-2.
[13] Shokri B, Mohebbi H, Mehrabani J. Amelioration of fructose-induced hepatic lipid accumulation by vitamin D3 supplementation and high-intensity interval training in male Sprague-Dawley rats[J]. Lipids Health Dis, 2024, 23(1):362. DOI: 10.1186/s12944-024-02347-y.
[14] Dewidar B, Mastrototaro L, Englisch C, et al. Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases[J]. EBioMedicine, 2023, 94:104714. DOI: 10.1016/j.ebiom.2023.104714.
[15] Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer[J]. JHEP Rep, 2022, 4(6):100479. DOI: 10.1016/j.jhepr.2022.100479.
[16] Ly LD, Xu S, Choi SK, et al. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes[J]. Exp Mol Med, 2017, 49(2): e291. DOI: 10.1038/emm.2016.157.
[17] Allameh A, Niayesh-Mehr R, Aliarab A, et al. Oxidative stress in liver pathophysiology and disease[J]. Antioxidants (Basel), 2023, 12(9):1653. DOI: 10.3390/antiox12091653.
[18] Sharma P, Nandave M, Nandave D, et al. Reactive oxygen species (ROS)-mediated oxidative stress in chronic liver diseases and its mitigation by medicinal plants[J]. Am J Transl Res, 2023, 15(11):6321-6341.
[19] Chen P, Yao L, Yuan M, et al. Mitochondrial dysfunction: a promising therapeutic target for liver diseases[J]. Genes Dis, 2023, 11(3):101115. DOI: 10.1016/j.gendis.2023.101115.
[20] Du D, Liu C, Qin M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma[J]. Acta Pharm Sin B, 2022, 12(2):558-580. DOI: 10.1016/j.apsb.2021.09.019.
[21] Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release[J]. Physiol Rev, 2014, 94(3): 909-950. DOI: 10.1152/physrev.00026.2013.
[22] Ajoolabady A, Kaplowitz N, Lebeaupin C, et al. Endoplasmic reticulum stress in liver diseases[J]. Hepatology, 2023, 77(2):619-639. DOI: 10.1002/hep.32562.
[23] Kang Z, Chen F, Wu W, et al. UPRmt and coordinated UPRER in type 2 diabetes[J]. Front Cell Dev Biol, 2022, 10:974083. DOI: 10.3389/fcell.2022.974083.
[24] Hendrix S, Zelcer N. A new SPRING in lipid metabolism[J]. Curr Opin Lipidol, 2023, 34(5):201-207. DOI: 10.1097/MOL.0000000000000894.
[25] Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c[J]. Diabetes Obes Metab, 2010, 12 Suppl 2:83-92. DOI: 10.1111/j.1463-1326.2010.01275.x.
[26] Kim C, Kim B. Anti-cancer natural products and their bioactive compounds inducing ER stress-mediated apoptosis: a review[J]. Nutrients, 2018, 10(8):1021. DOI: 10.3390/nu10081021.
[27] Tang H, Kang R, Liu J, et al. ATF4 in cellular stress, ferroptosis, and cancer[J]. Arch Toxicol, 2024, 98(4):1025-1041. DOI: 10.1007/s00204-024-03681-x.
[28] Ding J, Ji R, Wang Z, et al. Cardiovascular protection of YiyiFuzi powder and the potential mechanisms through modulating mitochondria-endoplasmic reticulum interactions[J]. Front Pharmacol, 2024, 15:1405545. DOI: 10.3389/fphar.2024.1405545.
[29] Branković M, Jovanović I, Dukić M, et al. Lipotoxicity as the leading cause of non-alcoholic steatohepatitis[J]. Int J Mol Sci, 2022, 23(9): 5146. DOI: 10.3390/ijms23095146.
[30] Apostolopoulou M, Gordillo R, Koliaki C, et al. Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis[J]. Diabetes Care, 2018, 41(6): 1235-1243. DOI: 10.2337/dc17-1318.
[31] Rivera-Andrade A, Álvarez CS. The importance of bile Acids in NAFLD: current evidence and future directions [J]. Ann Hepatol, 2022, 27(6):100773. DOI: 10.1016/j.aohep.2022.100773.
[32] Rui L. Energy metabolism in the liver[J]. Compr Physiol, 2014, 4(1):177-197. DOI: 10.1002/cphy.c130024.
[33] Yang W, Zhu L, Lai S, et al. Cimifugin ameliorates lipotoxicity-induced hepatocyte damage and steatosis through TLR4/p38 MAPK- and SIRT1-involved pathways[J]. Oxid Med Cell Longev, 2022, 2022:4557532. DOI: 10.1155/2022/4557532.
[34] Gao H, Jin Z, Bandyopadhyay G, et al. MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH[J]. Cell Metab, 2022, 34(7):978-990.e4. DOI: 10.1016/j.cmet.2022.05.008.
[35] Cai ZL, Wang LY, Zhang BY, et al. Mediterranean diet for cardiovascular disease: an evidence mapping study[J]. Public Health Nutr, 2024, 27(1):e118. DOI: 10.1017/S1368980024000776.
[36] Muffone ARMC, de Oliveira Lübke PDP, Rabito EI. Mediterranean diet and infertility: a systematic review with meta-analysis of cohort studies[J]. Nutr Rev, 2023, 81(7):775-789. DOI: 10.1093/nutrit/nuac087.
[37] Sakasai-Sakai A, Takata T, Takino JI, et al. The relevance of toxic AGEs (TAGE) cytotoxicity to NASH pathogenesis: a mini-review[J]. Nutrients, 2019, 11(2):462. DOI: 10.3390/nu11020462.
[38] Berná G, Romero-Gomez M. The role of nutrition in non-alcoholic fatty liver disease: pathophysiology and management[J]. Liver Int, 2020, 40 Suppl 1:102-108. DOI: 10.1111/liv.14360.
[39] Salman MA, Salman AA, Abdelsalam A, et al. Laparoscopic sleeve gastrectomy on the horizon as a promising treatment modality for NAFLD[J]. Obes Surg, 2020, 30(1):87-95. DOI: 10.1007/s11695-019-04118-6.
[40] Esquivel CM, Garcia M, Armando L, et al. Laparoscopic sleeve gastrectomy resolves NAFLD: another formal indication for bariatric surgery? [J] Obes Surg, 2018, 28(12):4022-4033. DOI: 10.1007/s11695-018-3466-7.
[41] Yeo SC, Ong WM, Cheng KSA, et al. Weight loss after bariatric surgery predicts an improvement in the non-alcoholic fatty liver disease (NAFLD) fibrosis score[J]. Obes Surg, 2019, 29(4):1295-1300. DOI: 10.1007/s11695-018-03676-5.
[42] Karlsson C, Wallenius K, Walentinsson A, et al. Identification of proteins associated with the early restoration of insulin sensitivity after biliopancreatic diversion[J]. J Clin Endocrinol Metab, 2020, 105(11): e4157-e4168. DOI: 10.1210/clinem/dgaa558.
[43] Slouha E, Elkersh EM, Shay A, et al. Significance of hormone alteration following bariatric surgery[J]. Cureus, 2023, 15(11): e49053. DOI: 10.7759/cureus.49053.
[44] Loosen SH, Demir M, Kunstein A, et al. Variables associated with increased incidence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes[J]. BMJ Open Diabetes Res Care, 2021, 9(1): e002243. DOI: 10.1136/bmjdrc-2021-002243.
[45] Kumar DP, Caffrey R, Marioneaux J, et al. The PPAR α/γ agonist saroglitazar improves insulin resistance and steatohepatitis in a diet induced animal model of nonalcoholic fatty liver disease[J]. Sci Rep, 2020, 10(1):9330. DOI: 10.1038/s41598-020-66458-z.
[46] Ma K, Saha PK, Chan L, et al. Farnesoid X receptor is essential for normal glucose homeostasis[J]. J Clin Invest, 2006, 116(4): 1102-1109. DOI: 10.1172/JCI25604.
[47] Patel K, Harrison SA, Elkhashab M, et al. Cilofexor, a nonsteroidal fxr agonist, in patients with noncirrhotic nash: a phase 2 randomized controlled trial[J]. Hepatology, 2020, 72(1):58-71. DOI: 10.1002/hep.31205.
[48] Zhang E, Zhao Y, Hu H. Impact of sodium glucose cotransporter 2 inhibitors on nonalcoholic fatty liver disease complicated by diabetes mellitus[J]. Hepatol Commun, 2021, 5(5): 736-748. DOI: 10.1002/hep4.1611.