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乳酸在代谢相关脂肪性肝病中的调控作用及其机制

孙雯可 伞吉爽 杨建成

引用本文:
Citation:

乳酸在代谢相关脂肪性肝病中的调控作用及其机制

DOI: 10.12449/JCH260829
基金项目: 

国家自然科学基金面上项目 (32573324);

国家自然科学基金面上项目 (32272965)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:孙雯可负责资料查找,撰写和修改论文;伞吉爽负责校对论文;杨建成负责指导修改论文并最终定稿。
详细信息
    通信作者:

    杨建成, syndyjc@syau.edu.cn (ORCID: 0000-0002-4509-0893)

Regulatory role and mechanism of lactate in metabolic dysfunction-associated fatty liver disease

Research funding: 

General Project of National Natural Science Foundation of China (32573324);

General Project of National Natural Science Foundation of China (32272965)

More Information
    Corresponding author: Yang Jiancheng, syndyjc@syau.edu.cn (ORCID: 0000-0002-4509-0893)
  • 摘要: 代谢相关脂肪性肝病(MAFLD)是一种在全球范围内患病率持续处于较高水平的慢性肝脏疾病,其发病机制涉及多系统代谢紊乱,目前尚未形成完整的调控理论体系。乳酸曾被认为是糖酵解途径的代谢终末废物,但近年来其作为关键信号分子的生物学功能持续被发掘。乳酸代谢失调与MAFLD发生发展的密切关联,已逐渐成为代谢性肝病领域的研究热点。本文系统介绍了乳酸代谢的核心通路及其调控模式,详细阐述了乳酸参与MAFLD发生发展的整体作用特征,重点评述了乳酸通过蛋白质乳酸化修饰等表观调控机制介导肝脏脂质代谢紊乱、驱动炎症级联反应的分子机制,并简要探讨了乳酸经肠-肝轴调控肝脏代谢稳态的潜在效应,归纳总结了乳酸代谢与MAFLD相关研究的最新进展。本文认为,靶向乳酸代谢通路是深化MAFLD病理生理机制理解的重要切入点,指出乳酸化修饰等非经典调控模式是未来值得重点突破的研究方向,并提出基于乳酸代谢网络开发MAFLD早期诊断标志物与干预靶点具有重要的理论价值与临床转化潜力。

     

  • [1] Huang D Q, Singal A G, Kono Y, et al. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer[J]. Cell Metab, 2022, 34( 7): 969- 977. DOI: 10.1016/j.cmet.2022.05.003.
    [2] Zhou Zhijia, Li Xinyue, Zheng Chao, et al. Advances in traditional Chinese medicine treatment of liver fibrosis in metabolic associated fatty liver disease[J]. J Clin Hepatol, 2025, 41( 10): 1968- 1974. DOI: 10.12449/JCH251002.

    周志佳, 李新月, 郑超, 等. 代谢相关脂肪性肝病肝纤维化的中医药治疗进展[J]. 临床肝胆病杂志, 2025, 41( 10): 1968- 1974. DOI: 10.12449/JCH251002.
    [3] Paik J M, Golabi P, Younossi Y, et al. Changes in the global burden of chronic liver diseases from 2012 to 2017: The growing impact of NAFLD[J]. Hepatology, 2020, 72( 5): 1605- 1616. DOI: 10.1002/hep.31173.
    [4] Devarbhavi H, Asrani S K, Arab J P, et al. Global burden of liver disease: 2023 update[J]. J Hepatol, 2023, 79( 2): 516- 537. DOI: 10.1016/j.jhep.2023.03.017.
    [5] Wang F S, Fan J G, Zhang Z, et al. The global burden of liver disease: The major impact of China[J]. Hepatology, 2014, 60( 6): 2099- 2108. DOI: 10.1002/hep.27406.
    [6] Oyabambi A O, Olaniyi K S, Soladoye A O, et al. Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats[J]. Environ Toxicol Pharmacol, 2020, 80: 103452. DOI: 10.1016/j.etap.2020.103452.
    [7] Wu G L, Dai Y F, Yan Y H, et al. The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs[J]. Eur J Pharmacol, 2022, 924: 174959. DOI: 10.1016/j.ejphar.2022.174959.
    [8] Rho H, Terry A R, Chronis C, et al. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis[J]. Cell Metab, 2023, 35( 8): 1406- 1423. DOI: 10.1016/j.cmet.2023.06.013.
    [9] Drolz A, Horvatits T, Rutter K, et al. Lactate improves prediction of short-term mortality in critically ill patients with cirrhosis: A multinational study[J]. Hepatology, 2019, 69( 1): 258- 269. DOI: 10.1002/hep.30151.
    [10] Nalbandian M, Takeda M. Lactate as a signaling molecule that regulates exercise-induced adaptations[J]. Biology, 2016, 5( 4): 38. DOI: 10.3390/biology5040038.
    [11] Robergs R A, McNulty C R, Minett G M, et al. Lactate, not lactic acid, is produced by cellular cytosolic energy catabolism[J]. Physiology(Bethesda), 2018, 33( 1): 10- 12. DOI: 10.1152/physiol.00033.2017.
    [12] Talasniemi J P, Pennanen S, Savolainen H, et al. Analytical investigation: Assay of D-lactate in diabetic plasma and urine[J]. Clin Biochem, 2008, 41( 13): 1099- 1103. DOI: 10.1016/j.clinbiochem.2008.06.011.
    [13] Fantin V R, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance[J]. Cancer Cell, 2006, 9( 6): 425- 434. DOI: 10.1016/j.ccr.2006.04.023.
    [14] Fang Chunyao, Zhou Suiqing, Yu Kai, et al. Research progress of lactate metabolism and lactylation in the diagnosis and treatment of hepatocellular carcinoma[J]. Chin J Dig Surg, 2026, 25( 4): 592- 597. DOI: 10.3760/cma.j.cn115610-20260224-00090.

    房春耀, 周岁清, 俞锴, 等. 乳酸代谢与乳酸化修饰在肝细胞癌诊疗中的研究进展[J]. 中华消化外科杂志, 2026, 25( 4): 592- 597. DOI: 10.3760/cma.j.cn115610-20260224-00090.
    [15] DeBerardinis R J, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis[J]. Proc Natl Acad Sci U S A, 2007, 104( 49): 19345- 19350. DOI: 10.1073/pnas.0709747104.
    [16] Bennis Y, Bodeau S, Batteux B, et al. A study of associations between plasma metformin concentration, lactic acidosis, and mortality in an emergency hospitalization context[J]. Crit Care Med, 2020, 48( 12): e1194- e1202. DOI: 10.1097/CCM.0000000000004589.
    [17] Jha M K, Lee I K, Suk K. Metabolic reprogramming by the pyruvate dehydrogenase kinase-lactic acid axis: Linking metabolism and diverse neuropathophysiologies[J]. Neurosci Biobehav Rev, 2016, 68: 1- 19. DOI: 10.1016/j.neubiorev.2016.05.006.
    [18] Soreze Y, Boutron A, Habarou F, et al. Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase[J]. Orphanet J Rare Dis, 2013, 8: 192. DOI: 10.1186/1750-1172-8-192.
    [19] Emhoff C A, Messonnier L A, Horning M A, et al. Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold[J]. J Appl Physiol(1985), 2013, 114( 3): 297- 306. DOI: 10.1152/japplphysiol.01202.2012.
    [20] Wang T X, Chen K, Yao W L, et al. Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance[J]. J Hepatol, 2021, 74( 5): 1038- 1052. DOI: 10.1016/j.jhep.2020.11.028.
    [21] Zhang L L, Xin C H, Wang S, et al. Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle[J]. Sci Adv, 2024, 10( 26): eadn4508. DOI: 10.1126/sciadv.adn4508.
    [22] Eskuri M, Kemi N, Kauppila J H. Monocarboxylate transporters 1 and 4 and MTCO1 in gastric cancer[J]. Cancers, 2021, 13( 9): 2142. DOI: 10.3390/cancers13092142.
    [23] Hu J Y, Cai M, Liu Y R, et al. The roles of GRP81 as a metabolic sensor and inflammatory mediator[J]. J Cell Physiol, 2020, 235( 12): 8938- 8950. DOI: 10.1002/jcp.29739.
    [24] Madaan A, Nadeau-Vallée M, Rivera J C, et al. Lactate produced during labor modulates uterine inflammation via GPR81(HCA1)[J]. Am J Obstet Gynecol, 2017, 216( 1): 60. DOI: 10.1016/j.ajog.2016.09.072.
    [25] Sun Z R, Han Y, Song S B, et al. Activation of GPR81 by lactate inhibits oscillatory shear stress-induced endothelial inflammation by activating the expression of KLF2[J]. IUBMB Life, 2019, 71( 12): 2010- 2019. DOI: 10.1002/iub.2151.
    [26] Laroche S, Stil A, Germain P, et al. Participation of L-lactate and its receptor HCAR1/GPR81 in neurovisual development[J]. Cells, 2021, 10( 7): 1640. DOI: 10.3390/cells10071640.
    [27] Wan Juan, Cheng Chunfang, Tang Shan, et al. Research progress of lactate as signal molecule[J]. Chin J Cell Biol, 2022, 44( 10): 1980- 1986. DOI: 10.11844/cjcb.2022.10.0011.

    万娟, 程春芳, 唐珊, 等. 乳酸作为信号分子作用的研究进展[J]. 中国细胞生物学学报, 2022, 44( 10): 1980- 1986. DOI: 10.11844/cjcb.2022.10.0011.
    [28] Ahmed K, Tunaru S, Tang C, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81[J]. Cell Metab, 2010, 11( 4): 311- 319. DOI: 10.1016/j.cmet.2010.02.012.
    [29] Chen S Y, Zhou L, Sun J Q, et al. The role of cAMP-PKA pathway in lactate-induced intramuscular triglyceride accumulation and mitochondria content increase in mice[J]. Front Physiol, 2021, 12: 709135. DOI: 10.3389/fphys.2021.709135.
    [30] Zhang D, Tang Z Y, Huang H, et al. Metabolic regulation of gene expression by histone lactylation[J]. Nature, 2019, 574( 7779): 575- 580. DOI: 10.1038/s41586-019-1678-1.
    [31] Li H, Li Z Y, Chen L, et al. PDHA1-mediated H3K18 lactylation is involved in arsenic-induced nonalcoholic fatty liver disease by activating the CD36-NLRP3 inflammasome axis[J]. J Hazard Mater, 2025, 498: 139852. DOI: 10.1016/j.jhazmat.2025.139852.
    [32] Kumar S, Sahu N, Jawaid T, et al. Dual role of lactate in human health and disease[J]. Front Physiol, 2025, 16: 1621358. DOI: 10.3389/fphys.2025.1621358.
    [33] Pohanka M. D-lactic acid as a metabolite: Toxicology, diagnosis, and detection[J]. Biomed Res Int, 2020, 2020: 3419034. DOI: 10.1155/2020/3419034.
    [34] Lazzeri C, Gensini G F, Sori A, et al. Dynamic behaviour of lactate values during mild hypothermia in patients with cardiac arrest[J]. Eur Heart J Acute Cardiovasc Care, 2014, 3( 2): 176- 182. DOI: 10.1177/2048872613514014.
    [35] Scheiner B, Lindner G, Reiberger T, et al. Acid-base disorders in liver disease[J]. J Hepatol, 2017, 67( 5): 1062- 1073. DOI: 10.1016/j.jhep.2017.06.023.
    [36] Ma Y L, Ke J F, Wang J W, et al. Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: A real-world study[J]. Front Endocrinol, 2023, 14: 1133991. DOI: 10.3389/fendo.2023.1133991.
    [37] Yu L, Bao S M, Zhu F, et al. Serum lactate dehydrogenase is a novel predictor for the severity in the patients with MAFLD: A cross-sectional study in Hefei, China[J]. Diabetes Metab Syndr Obes, 2025, 18: 345- 361. DOI: 10.2147/DMSO.S492153.
    [38] Yao Z Y, Gong Y, Chen W B, 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.
    [39] Tao R Y, Stöhr O, Tok O, et al. Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance[J]. Nat Commun, 2025, 16( 1): 11595. DOI: 10.1038/s41467-025-66296-5.
    [40] Lin Y J, Bai M J, Wang S, et al. Lactate is a key mediator that links obesity to insulin resistance via modulating cytokine production from adipose tissue[J]. Diabetes, 2022, 71( 4): 637- 652. DOI: 10.2337/db21-0535.
    [41] Gou Y N, Li A H, Dong X Y, et al. Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease[J]. Genes Dis, 2025, 12( 4): 101554. DOI: 10.1016/j.gendis.2025.101554.
    [42] Liu Y, Zhou R, Guo Y F, et al. Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining[J]. Cell Metab, 2025, 37( 4): 824- 841. DOI: 10.1016/j.cmet.2024.12.005.
    [43] Wang X Y, Chen H, Zhu W F, et al. Akebia trifoliata extracts attenuate liver injury via gut-liver axis in a murine model of nonalcoholic fatty liver disease with low-grade colitis[J]. Food Res Int, 2025, 208: 116202. DOI: 10.1016/j.foodres.2025.116202.
    [44] Song W, Hu J H, Zhu L N, et al. Inulin alleviates HFD-induced NAFLD by hepatic macrophage polarization and lipid metabolism via gut-liver axis[J]. Food Sci Hum Wellness, 2025, 14( 2): 9250040. DOI: 10.26599/fshw.2024.9250040.
    [45] Kuang J L, Wang J Y, Li Y T, et al. Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis[J]. Cell Metab, 2023, 35( 10): 1752- 1766. DOI: 10.1016/j.cmet.2023.07.011.
    [46] Zhao H, Zhou J, Yuan L, et al. Exploring the alleviating effects of Bifidobacterium metabolite lactic acid on non-alcoholic steatohepatitis through the gut-liver axis[J]. Front Microbiol, 2025, 15: 1518150. DOI: 10.3389/fmicb.2024.1518150.
    [47] Zhu Y Y, Dong X, Zhou H, et al. Gut microbiota colonization in early life influences susceptibility to adulthood hepatic lipid accumulation in high-fat-diet-fed mice[J]. Adv Sci(Weinh), 2025, 12( 21): e2412827. DOI: 10.1002/advs.202412827.
    [48] Sarkar S, Saha P, Seth R K, et al. Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease[J]. Comp Biochem Physiol C Toxicol Pharmacol, 2020, 238: 108854. DOI: 10.1016/j.cbpc.2020.108854.
    [49] Gao R X, Li Y, Xu Z M, et al. Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease[J]. Hepatology, 2023, 78( 6): 1800- 1815. DOI: 10.1097/HEP.0000000000000279.
    [50] Jeppesen J B, Mortensen C, Bendtsen F, et al. Lactate metabolism in chronic liver disease[J]. Scand J Clin Lab Invest, 2013, 73( 4): 293- 299. DOI: 10.3109/00365513.2013.773591.
    [51] Ha T S, Shin T G, Jo I J, et al. Lactate clearance and mortality in septic patients with hepatic dysfunction[J]. Am J Emerg Med, 2016, 34( 6): 1011- 1015. DOI: 10.1016/j.ajem.2016.02.053.
    [52] Li J, Wang T X, Xia J, et al. Enzymatic and nonenzymatic protein acetylations control glycolysis process in liver diseases[J]. FASEB J, 2019, 33( 11): 11640- 11654. DOI: 10.1096/fj.201901175R.
    [53] Dufour J F, Anstee Q M, Bugianesi E, et al. Current therapies and new developments in NASH[J]. Gut, 2022, 71( 10): 2123- 2134. DOI: 10.1136/gutjnl-2021-326874.
    [54] Roland C L, Arumugam T, Deng D F, et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival[J]. Cancer Res, 2014, 74( 18): 5301- 5310. DOI: 10.1158/0008-5472.CAN-14-0319.
    [55] Li J Y, Chen X C, Song S Y, et al. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD[J]. Cell Rep, 2025, 44( 3): 115350. DOI: 10.1016/j.celrep.2025.115350.
    [56] Jiao Q L, Ren Y D, Teng X Y, et al. Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression[J]. Hepatol Int, 2026, 20( 3): 646- 663. DOI: 10.1007/s12072-025-10978-1.
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  • 收稿日期:  2025-12-10
  • 录用日期:  2026-02-09
  • 出版日期:  2026-08-25
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