生长分化因子15调控代谢相关脂肪性肝病合并2型糖尿病的作用机制研究进展

doi:10.3969/j.issn.1004-583X.2026.09.013

摘要/Abstract

摘要：

代谢相关脂肪性肝病(MAFLD)已成为全球范围内发病率最高的慢性肝病之一,影响着全球约三分之一人口,且发病年龄逐渐年轻化,同时多伴有2型糖尿病(T2DM)、超重/肥胖或代谢综合征,发病机制复杂。因此,为了阻止MAFLD及其继发病症进展,亟需探索新的潜在药物作用靶点。生长分化因子15(GDF-15)作为转化生长因子β(TGF-β)超家族的应激反应细胞因子,在肥胖和糖尿病等代谢紊乱中发挥重要调控作用。在MAFLD合并T2DM中,GDF-15可改善胰岛素敏感性、促进糖脂代谢平衡、通过抑制食欲减轻体重、激活脂肪酸β氧化、抑制肝细胞肥大及纤维化基因表达、缓解脂肪组织慢性炎症等。本文系统综述GDF-15在MAFLD合并T2DM病中的分子机制及潜在价值,为疾病理解与临床治疗提供参考。

关键词: 非酒精性脂肪性肝病, 糖尿病,2型, 生长分化因子15, 胰岛素敏感性, 炎症

中图分类号:

R575.5

白慧慧, 张晓萌, 牛佳乐, 卢亚敏. 生长分化因子15调控代谢相关脂肪性肝病合并2型糖尿病的作用机制研究进展[J]. 临床荟萃, 2026, 41(9): 859-864.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.lchc.cn/CN/10.3969/j.issn.1004-583X.2026.09.013

https://www.lchc.cn/CN/Y2026/V41/I9/859

图/表 1

参考文献 46

[1]	Gish R, Fan JG, Dossaji Z, et al. Review of current and new drugs for the treatment of metabolic-associated fatty liver disease[J]. Hepatol Int, 2024, 18(Suppl 2):977-989. doi: 10.1007/s12072-024-10698-y.
[2]	Lago-Sampedro A, Oualla-Bachiri W, García-Serrano S, et al. Protective effect of high adherence to mediterranean diet on the risk of incident type-2 diabetes in subjects with MAFLD: The Di@bet.es Study[J]. Nutrients, 2024, 16(21):3788. doi: 10.3390/nu16213788.
[3]	Kim H, Lee DS, An TH, et al. Metabolic spectrum of liver failure in type 2 diabetes and obesity: From NAFLD to NASH to HCC[J]. Int J Mol Sci, 2021, 22(9):4495. doi: 10.3390/ijms22094495.
[4]	Zhang S, Zeng X F, Borné Y, et al. Adherence to the EAT-Lancet reference diet and risk of type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and their co-occurrence[J]. Food Funct, 2025, 16(17):6773-6785. doi: 10.1039/d4fo05852f. pmid: 40793982
[5]	Di Pastena F, Pond G, Tsakiridis EE, et al. Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy[J]. Radiat Oncol, 2024, 19(1): 155.doi: 10.1186/s13014-024-02546-y. pmid: 39511611
[6]	Wang D, Day EA, Townsend LK, et al. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease[J]. Nat Rev Endocrinol, 2021, 17(10): 592-607.doi: 10.1038/s41574-021-00529-7. pmid: 34381196
[7]	Yang C, Chen H, Huang X, et al. GDF15: An emerging disease target and biomarker of metabolic diseases[J]. J Endocrinol Invest, 2025, 48(11):2563-2576. doi: 10.1007/s40618-025-02636-y.
[8]	Lu JF, Zhu MQ, Xia B, et al. GDF15 is a major determinant of ketogenic diet-induced weight loss[J]. Cell Metab, 2024, 36(2): 454-456.doi: 10.1016/j.cmet.2024.01.004. pmid: 38325339
[9]	Wang Q, Farhadipour M, Thijs T, et al. Bitter-tasting drugs tune GDF15 and GLP-1 expression via bitter taste or motilin receptors in the intestine of patients with obesity[J]. Mol Metab, 2024, 88: 102002.doi: 10.1016/j.molmet.2024.102002.
[10]	Hsu JY, Crawley S, Chen M, et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15[J]. Nature, 2017, 550(7675): 255-259.doi: 10.1038/nature24042.
[11]	Olsen OE, Skjærvik A, Størdal B F, et al. TGF-β contamination of purified recombinant GDF15[J]. PLoS One, 2017, 12(11): e0187349.doi: 10.1371/journal.pone.0187349.
[12]	Govaere O, Cockell S, Tiniakos D, et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis[J]. Sci Transl Med, 2020, 12(572):eaba4448. doi: 10.1126/scitranslmed.aba4448.
[13]	Li D, Zhang H, Zhong Y. Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice[J]. Biochem Biophys Res Commun, 2018, 498(3): 388-394.doi: 10.1016/j.bbrc.2017.08.096.
[14]	Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates[J]. Nat Med, 2017, 23(10): 1150-1157. doi: 10.1038/nm.4392 pmid: 28846097
[15]	Wang D, Townsend LK, Desormeaux GJ, et al. GDF15 promotes weight loss by enhancing energy expenditure in muscle[J]. Nature, 2023, 619(7968): 143-150.doi: 10.1038/nm.4392.
[16]	Chrysovergis K, Wang X, Kosak J, et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism[J]. Int J Obes (Lond), 2014, 38(12):1555-1564. doi: 10.1038/ijo.2014.27.
[17]	Zhang M, Sun W, Qian J, et al. Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver[J]. Redox Biol, 2018, 16:87-96. doi: 10.1016/j.redox.2018.01.013. pmid: 29482168
[18]	Zhang Z, Xu X, Tian W, et al. ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation[J]. J Hepatol, 2020, 72(5): 976-989.doi: 10.1016/j.jhep.2019.12.004. pmid: 31857195
[19]	Kim KH, Kim SH, Han DH, et al. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice[J]. Sci Rep, 2018, 8(1): 6789. doi: 10.1038/s41598-018-25098-0. pmid: 29717162
[20]	Koo BK, Um SH, Seo DS, et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease[J]. Liver Int, 2018, 38(4): 695-705.doi: 10.1111/liv.13587. pmid: 28898507
[21]	Wang Y, Chen C, Chen J, et al. Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation[J]. Redox Biol, 2022, 52: 102322.doi: 10.1016/j.redox.2022.102322.
[22]	Li X, Huai Q, Zhu C, et al. GDF15 ameliorates liver fibrosis by metabolic reprogramming of macrophages to acquire anti-inflammatory properties[J]. Cell Mol Gastroenterol Hepatol, 2023, 16(5): 711-734.doi: 10.1016/j.jcmgh.2023.07.009. pmid: 37499753
[23]	Laurens C, Parmar A, Murphy E, et al. Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans[J]. JCI Insight, 2020, 5(6):e131870. doi: 10.1172/jci.insight.131870.
[24]	Xiong Y, Walker K, Min X, et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys[J]. Sci Transl Med, 2017, 9(412):eaan8732. doi: 10.1126/scitranslmed.aan8732.
[25]	Wang X, Chrysovergis K, Kosak J, et al. Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity[J]. Obesity (Silver Spring), 2014, 22(5): 1256-1263. doi: 10.1002/oby.20638.
[26]	Lertpatipanpong P, Lee J, Kim I, et al. The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice[J]. Sci Rep, 2021, 11(1): 15027. doi: 10.1038/s41598-021-94581-y. pmid: 34294853
[27]	Lee SE, Kang SG, Choi MJ, et al. Growth differentiation factor 15 mediates systemic glucose regulatory action of t-helper type 2 cytokines[J]. Diabetes, 2017, 66(11): 2774-2788.doi: 10.2337/db17-0333. pmid: 28874416
[28]	Schernthaner-Reiter MH, Itariu BK, Krebs M, et al. GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism[J]. Nutr Metab Cardiovasc Dis, 2019, 29(4):334-342. doi: 10.1016/j.numecd.2018.12.008.
[29]	Asrih M, Dusaulcy R, Gosmain Y, et al. Growth differentiation factor-15 prevents glucotoxicity and connexin-36 downregulation in pancreatic beta-cells[J]. Mol Cell Endocrinol, 2022, 541: 111503. doi: 10.1016/j.mce.2021.111503.
[30]	Zhang H, Mulya A, Nieuwoudt S, et al. GDF15 mediates the effect of skeletal muscle contraction on glucose-stimulated insulin secretion[J]. Diabetes, 2023, 72(8): 1070-1082.doi: 10.2337/db22-0019. pmid: 37224335
[31]	Chang KC, Liu PF, Chang CH, et al. The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases[J]. Cell Biosci, 2022, 12(1): 1.doi: 10.1186/s13578-021-00736-9.
[32]	Aguilar-Recarte D, Barroso E, Gumà A, et al. GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK[J]. Cell Rep, 2021, 36(6): 109501.doi: 10.1016/j.celrep.2021.109501.
[33]	Li J, Yang L, Qin W, et al. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus[J]. PLoS One, 2013, 8(6): e65549. doi: 10.1371/journal.pone.0065549.
[34]	Ray N, Park SJ, Jung H, et al. Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming[J]. Commun Biol, 2023, 6(1): 602.doi: 10.1038/s42003-023-04965-1. pmid: 37270567
[35]	Kim J, Kim SH, Kang H, et al. TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response[J]. Nat Metab, 2021, 3(3): 410-427.doi: 10.1038/s42255-021-00368-w. pmid: 33758420
[36]	Wang Y, Chen J, Sang T, et al. NAG-1/GDF15 protects against streptozotocin-induced type 1 diabetes by inhibiting apoptosis, preserving beta-cell function, and suppressing inflammation in pancreatic islets[J]. Mol Cell Endocrinol, 2022, 549: 111643.doi: 10.1016/j.mce.2022.111643.
[37]	Chen J, Peng H, Chen C, et al. NAG-1/GDF15 inhibits diabetic nephropathy via inhibiting AGE/RAGE-mediated inflammation signaling pathways in C57BL/6 mice and HK-2 cells[J]. Life Sci, 2022, 311(Pt A): 121142.doi: 10.1016/j.lfs.2022.121142.
[38]	Jung SB, Choi MJ, Ryu D, et al. Reduced oxidative capacity in macrophages results in systemic insulin resistance[J]. Nat Commun, 2018, 9(1): 1551.doi: 10.1038/s41467-018-03998-z.
[39]	Sjøberg KA, Sigvardsen CM, Alvarado-Diaz A, et al. GDF15 increases insulin action in the liver and adipose tissue via a β-adrenergic receptor-mediated mechanism[J]. Cell Metab, 2023, 35(8): 1327-1340.e5. doi: 10.1016/j.cmet.2023.06.016.
[40]	Jurado-Aguilar J, Barroso E, Bernard M, et al. GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway[J]. Metabolism, 2024, 152: 155772.doi: 10.1016/j.metabol.2023.155772.
[41]	Klein AB, Nicolaisen TS, Johann K, et al. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance[J]. Cell Rep, 2022, 40(8): 111258.doi: 10.1016/j.celrep.2022.111258.
[42]	Aguilar-Recarte D, Barroso E, Zhang M, et al. A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects[J]. Pharmacol Res, 2023, 187: 106578.doi: 10.1016/j.phrs.2022.106578.
[43]	Patel S, Haider A, Alvarez-Guaita A, et al. Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice[J]. Mol Metab, 2022, 65: 101589.doi: 10.1016/j.molmet.2022.101589.
[44]	Zhang Y, Zhao X, Dong X, et al. Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates[J]. Cell Metab, 2023, 35(2): 287-298.e4.doi: 10.1016/j.cmet.2023.01.001.
[45]	Richter MM, Kemp IM, Heebøll S, et al. Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms[J]. Metabolism, 2024, 156: 155915.doi: 10.1016/j.metabol.2024.155915.
[46]	Breit SN, Manandhar R, Zhang HP, et al. GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway[J]. Cell Metab, 2023, 35(8): 1341-1355.e3. doi: 10.1016/j.cmet.2023.06.009. pmid: 37433299

生长分化因子15调控代谢相关脂肪性肝病合并2型糖尿病的作用机制研究进展

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 1

参考文献 46

相关文章 15

编辑推荐

Metrics

本文评价

[1]	程静文, 陈雪英, 刘旭, 高荣华. 冠状动脉慢血流的临床预测指标与病理机制研究进展[J]. 临床荟萃, 2026, 41(6): 562-567.
[2]	王天慧, 吕慧, 冯利菲, 陈亚杰. 血清FABP5、SII、VEGF水平与肝癌患者预后的关系分析[J]. 临床荟萃, 2026, 41(5): 399-405.
[3]	林涛, 吴玮君. 中高海拔地区帕金森病非运动症状的临床特征谱及其与肠道菌群-肠-脑轴关联机制[J]. 临床荟萃, 2026, 41(4): 301-306.
[4]	姜少利, 闫国胜, 李丽丽. 终末期维持性血液透析患者营养不良-炎症复合综合征发生情况及其危险因素[J]. 临床荟萃, 2026, 41(4): 312-317.
[5]	车晓娜, 慕淑丽, 刘宁宁, 崔文婷, 陈金玥, 魏小果. 基于肠道菌群治疗代谢相关脂肪性肝病的研究进展[J]. 临床荟萃, 2026, 41(4): 352-362.
[6]	刘一坤, 张明, 刘倩, 孙绍婷, 李媛媛, 杜书同. 连续性肾脏替代治疗在脓毒症合并急性肾损伤中的研究进展[J]. 临床荟萃, 2026, 41(4): 374-379.
[7]	汤思颖, 贾君萍, 唐雨婷, 郑玉琴, 孔悦. 膳食炎症指数与肺癌风险相关性的meta分析[J]. 临床荟萃, 2026, 41(3): 197-204.
[8]	姜俊辰, 郭蓉娟, 张帆, 刘佳霖. MAPK信号通路在脑出血中的研究进展[J]. 临床荟萃, 2026, 41(3): 269-273.
[9]	贾砚秋, 陈伟红, 吕佩源. 食源性生物活性成分的神经保护作用研究进展[J]. 临床荟萃, 2026, 41(3): 274-279.
[10]	曹乐, 赵宇鹏, 薛凌. 系统免疫炎症指数对射血分数降低型心衰患者发生主要不良心血管事件的预测价值[J]. 临床荟萃, 2026, 41(2): 122-127.
[11]	李云翔, 李淑琼, 丁雪, 王思博, 王建军. TLR2与肺炎支原体感染及药物治疗的研究进展[J]. 临床荟萃, 2025, 40(6): 553-557.
[12]	刘萍, 于猛, 刘明新, 李文锋. 血常规衍生的新型炎症指标与急性前壁ST段抬高型心肌梗死患者PCI术后院内发生不良心血管事件的相关性[J]. 临床荟萃, 2025, 40(5): 400-407.
[13]	肇雪婷, 白佳雯, 孙军. 代谢相关脂肪性肝病肝纤维化危险因素分析及构建预测模型[J]. 临床荟萃, 2025, 40(5): 417-422.
[14]	范玉雯, 宋佳, 黄盼娜, 张晓岚. 淋巴细胞归巢在炎症性肠病中的作用及相关治疗靶点[J]. 临床荟萃, 2025, 40(5): 468-472.
[15]	祝昌昊, 张洪鹏. 炎症相关信号通路在类风湿关节炎中的研究进展[J]. 临床荟萃, 2025, 40(5): 477-480.