脂肪组织来源的细胞外囊泡在肝脏疾病中的作用机制

敖晓艳; 凡小丽; 周乐雨

doi:10.12449/JCH260734

脂肪组织来源的细胞外囊泡在肝脏疾病中的作用机制

DOI: 10.12449/JCH260734

四川大学华西医院消化系统肿瘤与肝病研究室，成都 610000

基金项目:

四川大学华西医院“启明星”青年人才科研启动基金 (HXQMX0010)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：敖晓艳、凡小丽负责撰写原稿，论文修改；周乐雨指导撰写文章并最后定稿。

详细信息

通信作者:
周乐雨， zhouleyu@scu.edu.cn （ORCID： 0000-0001-5421-4117）

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出版历程
- 收稿日期: 2025-11-22
- 录用日期: 2026-01-04
- 出版日期: 2026-07-25

Mechanism of action of adipose tissue-derived extracellular vesicles in liver diseases

Laboratory of Gastrointestinal Cancer and Liver Disease，West China Hospital，Sichuan University，Chengdu 610000，China

Research funding:

West China Hospital “Venus” Young Talent Research Start-up Grant (HXQMX0010)

More Information

Corresponding author: Zhou Leyu， zhouleyu@scu.edu.cn （ORCID： 0000-0001-5421-4117）

摘要

摘要: 脂肪组织作为重要的内分泌与免疫器官，其功能失调与多种肝脏疾病的发生发展密切相关。除分泌经典的脂肪因子外，脂肪组织来源的细胞外囊泡已成为其调控远端器官功能的关键信使。本文系统阐述了脂肪组织来源的细胞外囊泡在肝脏疾病中的调控作用：白色脂肪组织通过其细胞外囊泡递送微RNA-103、分化抗原36等致病分子，驱动肝脏胰岛素抵抗、脂质堆积及纤维化进程；而棕色脂肪组织则通过其细胞外囊泡传递微RNA-132-3p等保护性信号，改善肝脏代谢稳态。本文总结了上述细胞外囊泡的核心作用机制，并展望了其作为疾病诊断生物标志物与创新治疗策略的潜力。
- 细胞外囊泡 /
- 脂肪组织 /
- 肝疾病
Abstract: Adipose tissue is a crucial endocrine and immune organ， and its functional dysregulation is closely associated with the development and progression of various liver diseases. In addition to the secretion of classical adipokines， adipose tissue-derived extracellular vesicles （EVs） have emerged as key messengers in its regulation of distal organ function. This review systematically elaborates on the regulatory role of adipose tissue-derived EVs in liver diseases， in which white adipose tissue delivers pathogenic molecules such as miR-103 and CD36 via its EVs and thus drives hepatic insulin resistance， lipid accumulation， and fibrosis， while brown adipose tissue transmits protective signals such as miR-132-3p through its EVs to improve hepatic metabolic homeostasis. This article also summarizes the core mechanisms of action of these EVs and discusses their potential as diagnostic biomarkers and innovative therapeutic strategies.
- Extracellular Vesicles /
- Adipose Tissue /
- Liver Diseases

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注： Akt，蛋白激酶B；CD36，分化抗原36；TGF-β，转化生长因子β；OCR，耗氧率；Srebf1，固醇调节元件结合转录因子1；miR，微RNA。

图 1 白色脂肪组织与棕色脂肪组织来源的细胞外囊泡在肝脏疾病中的作用

Figure 1. The roles of white and brown adipose tissue-derived extracellular vesicles in liver diseases

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表 1 脂肪细胞外囊泡中关键货物分子及其在肝脏疾病中的作用机制

Table 1. Key cargo molecules in adipose extracellular vesicles and their mechanisms of action in liver diseases

分子类型	关键分子	脂肪来源	肝脏细胞中的主要功能/效应	作用的靶点与分子机制	参考文献
表面蛋白	CD36	WAT	促进肝细胞脂质积累和炎症	作为脂肪酸转运蛋白，被EV递送至肝细胞，直接增强脂肪酸摄取	［33］
蛋白质内容物	脂联素	WAT（瘦个体）	改善肝脏胰岛素抵抗和炎症	附着于sEV表面被运输至肝脏，发挥其经典的胰岛素增敏和抗炎作用	［38］
蛋白质内容物	抵抗素	WAT	诱导肝脂肪变性和内质网应激	抑制肝细胞中pAMPKα Thr172的磷酸化，触发内质网应激	［40］
lncRNA内容物	LINC01705	WAT	在高糖条件下促进肝细胞脂质沉积	作为ceRNA吸附miR-552-3p，解除其对LXR的抑制，激活LXR信号通路	［39］
miRNA内容物	miR-378a-3p	BAT	冷应激时促进肝脏糖异生	靶向p110α（PI3K催化亚基），增强肝脏糖异生能力	［42］
	miR-132-3p	BAT	抑制肝脏脂肪生成	靶向Srebf1 mRNA，抑制其表达，从而下调下游脂生成基因	［43］
	miR-206-3p	BAT	抑制肝脏脂肪生成	靶向G6PD与Tkt的3’UTR，抑制磷酸戊糖通路，减少NADPH供应，从而抑制脂肪酸从头合成	［44］
	miR-451	BAT	提高肝细胞胰岛素敏感性	通过抑制其靶基因（如Ywhaz），激活 AMPK通路	［45］
注：EV，细胞外囊泡；sEV，小细胞外囊泡；AMPK，腺苷一磷酸活化的蛋白质激酶；mTOR，哺乳动物雷帕霉素靶蛋白；ceRNA，竞争性内源RNA；LXR，肝X受体；PI3K，磷脂酰肌醇3-激酶；Srebf1，固醇调节元件结合转录因子1；UTR，非翻译区；G6PD，葡萄糖-6-磷酸脱氢酶；Tkt，转酮酶；NADPH，还原型烟酰胺腺嘌呤二核苷酸磷酸；lncRNA，长链非编码RNA；miRNA/miR，微RNA；WAT，白色脂肪组织；BAT，棕色脂肪组织；CD36，分化簇36。

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参考文献(56)

[1]	Asrani S K, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world[J]. J Hepatol, 2019, 70( 1): 151- 171. DOI: 10.1016/j.jhep.2018.09.014.
[2]	Griffin C, Agbim U, Ramani A, et al. Underestimation of cirrhosis-related mortality in the medicare eligible population, 1999-2018[J]. Clin Gastroenterol Hepatol, 2023, 21( 1): 223- 225. e 3. DOI: 10.1016/j.cgh.2021.10.036.
[3]	Hagström H, Thiele M, Roelstraete B, et al. Mortality in biopsy-proven alcohol-related liver disease: A population-based nationwide cohort study of 3453 patients[J]. Gut, 2021, 70( 1): 170- 179. DOI: 10.1136/gutjnl-2019-320446.
[4]	Gavaldà-Navarro A, Villarroya J, Cereijo R, et al. The endocrine role of brown adipose tissue: An update on actors and actions[J]. Rev Endocr Metab Disord, 2022, 23( 1): 31- 41. DOI: 10.1007/s11154-021-09640-6.
[5]	Yáñez-Mó M, Siljander P R M, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions[J]. J Extracell Vesicles, 2015, 4( 1): 27066. DOI: 10.3402/jev.v4.27066.
[6]	Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses[J]. Nat Rev Immunol, 2009, 9( 8): 581- 593. DOI: 10.1038/nri2567.
[7]	van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles[J]. Nat Rev Mol Cell Biol, 2018, 19( 4): 213- 228. DOI: 10.1038/nrm.2017.125.
[8]	Akers J C, Gonda D, Kim R, et al. Biogenesis of extracellular vesicles(EV): Exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies[J]. J Neurooncol, 2013, 113( 1): 1- 11. DOI: 10.1007/s11060-013-1084-8.
[9]	Abels E R, Breakefield X O. Introduction to extracellular vesicles: Biogenesis, RNA cargo selection, content, release, and uptake[J]. Cell Mol Neurobiol, 2016, 36( 3): 301- 312. DOI: 10.1007/s10571-016-0366-z.
[10]	Welsh J A, Goberdhan D C I, O'Driscoll L, et al. Minimal information for studies of extracellular vesicles(MISEV2023): From basic to advanced approaches[J]. J Extracell Vesicles, 2024, 13( 2): e12404. DOI: 10.1002/jev2.12404.
[11]	Ostrowski M, Carmo N B, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway[J]. Nat Cell Biol, 2010, 12( 1): 19- 30. DOI: 10.1038/ncb2000.
[12]	Yanatori I, Richardson D R, Dhekne H S, et al. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles[J]. Blood, 2021, 138( 16): 1490- 1503. DOI: 10.1182/blood.2021010995.
[13]	Salunkhe S, Dheeraj, Basak M, et al. Surface functionalization of exosomes for target-specific delivery and in vivo imaging& tracking: Strategies and significance[J]. J Control Release, 2020, 326: 599- 614. DOI: 10.1016/j.jconrel.2020.07.042.
[14]	Subra C, Laulagnier K, Perret B, et al. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies[J]. Biochimie, 2007, 89( 2): 205- 212. DOI: 10.1016/j.biochi.2006.10.014.
[15]	Crescitelli R, Lässer C, Szabó T G, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: Apoptotic bodies, microvesicles and exosomes[J]. J Extracell Vesicles, 2013, 2( 1): 20677. DOI: 10.3402/jev.v2i0.20677.
[16]	Nolte-'t Hoen E N, Buermans H P, Waasdorp M, et al. Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions[J]. Nucleic Acids Res, 2012, 40( 18): 9272- 9285. DOI: 10.1093/nar/gks658.
[17]	Tkach M, Théry C. Communication by extracellular vesicles: Where we are and where we need to go[J]. Cell, 2016, 164( 6): 1226- 1232. DOI: 10.1016/j.cell.2016.01.043.
[18]	Kourembanas S. Exosomes: Vehicles of intercellular signaling, biomarkers, and vectors of cell therapy[J]. Annu Rev Physiol, 2015, 77: 13- 27. DOI: 10.1146/annurev-physiol-021014-071641.
[19]	Zipkin M. Big pharma buys into exosomes for drug delivery[J]. Nat Biotechnol, 2020, 38: 1226- 1228. DOI: 10.1038/s41587-020-0725-7.
[20]	Li W H, Li C Y, Zhou T, et al. Role of exosomal proteins in cancer diagnosis[J]. Mol Cancer, 2017, 16( 1): 145. DOI: 10.1186/s12943-017-0706-8.
[21]	Hoshino A, Kim H S, Bojmar L, et al. Extracellular vesicle and particle biomarkers define multiple human cancers[J]. Cell, 2020, 182( 4): 1044- 1061.e18. DOI: 10.1016/j.cell.2020.07.009.
[22]	Koeck E S, Iordanskaia T, Sevilla S, et al. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: A novel paradigm for obesity-related liver disease[J]. J Surg Res, 2014, 192( 2): 268- 275. DOI: 10.1016/j.jss.2014.06.050.
[23]	Mulcahy L A, Pink R C, Carter D R F. Routes and mechanisms of extracellular vesicle uptake[J]. J Extracell Vesicles, 2014, 3( 1): 24641. DOI: 10.3402/jev.v3.24641.
[24]	Zhou X Y, Li Z L, Qi M H, et al. Brown adipose tissue-derived exosomes mitigate the metabolic syndrome in high fat diet mice[J]. Theranostics, 2020, 10( 18): 8197- 8210. DOI: 10.7150/thno.43968.
[25]	Rosen E D, Spiegelman B M. What we talk about when we talk about fat[J]. Cell, 2014, 156( 1-2): 20- 44. DOI: 10.1016/j.cell.2013.12.012.
[26]	Kwok K H, Lam K S, Xu A M. Heterogeneity of white adipose tissue: Molecular basis and clinical implications[J]. Exp Mol Med, 2016, 48( 3): e215. DOI: 10.1038/emm.2016.5.
[27]	Saely C H, Geiger K, Drexel H. Brown versus white adipose tissue: A mini-review[J]. Gerontology, 2012, 58( 1): 15- 23. DOI: 10.1159/000321319.
[28]	Ren Jianhuan, Han Xue, Xu Jiaxin, et al. The role of the cellular repressor of E1A-stimulated genes in cold-exposed fat browning and mitochondrial biogenesis[J]. Chin J Med Offic, 2025, 53( 8): 799- 804. DOI: 10.16680/j.1671-3826.2025.08.07. 任建焕, 韩雪, 徐嘉欣, 等. E1A激活基因阻遏子在冷暴露脂肪棕色化及线粒体生物发生中作用[J]. 临床军医杂志, 2025, 53( 8): 799- 804. DOI: 10.16680/j.1671-3826.2025.08.07.
[29]	Cypess A M, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans[J]. N Engl J Med, 2009, 360( 15): 1509- 1517. DOI: 10.1056/nejmoa0810780.
[30]	Wu J, Boström P, Sparks L M, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human[J]. Cell, 2012, 150( 2): 366- 376. DOI: 10.1016/j.cell.2012.05.016.
[31]	Vázquez-Vela M E F, Torres N, Tovar A R. White adipose tissue as endocrine organ and its role in obesity[J]. Arch Med Res, 2008, 39( 8): 715- 728. DOI: 10.1016/j.arcmed.2008.09.005.
[32]	Kershaw E E, Flier J S. Adipose tissue as an endocrine organ[J]. J Clin Endocrinol Metab, 2004, 89( 6): 2548- 2556. DOI: 10.1210/jc.2004-0395.
[33]	Yan C H, Tian X X, Li J Y, et al. A high-fat diet attenuates AMPK α1 in adipocytes to induce exosome shedding and nonalcoholic fatty liver development in vivo[J]. Diabetes, 2021, 70( 2): 577- 588. DOI: 10.2337/db20-0146.
[34]	Fuchs A, Samovski D, Smith G I, et al. Associations among adipose tissue immunology, inflammation, exosomes and insulin sensitivity in people with obesity and nonalcoholic fatty liver disease[J]. Gastroenterology, 2021, 161( 3): 968- 981. e 12. DOI: 10.1053/j.gastro.2021.05.008.
[35]	Kranendonk M E, Visseren F L, van Herwaarden J A, et al. Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells[J]. Obesity(Silver Spring), 2014, 22( 10): 2216- 2223. DOI: 10.1002/oby.20847.
[36]	Kim Y, Son T, Park J, et al. Role of exosomes derived from adipose tissue under obese conditions in skeletal muscle and liver cells: Commonalities and differences[J]. Mol Nutr Food Res, 2022, 66( 23): e2200358. DOI: 10.1002/mnfr.202200358.
[37]	Lago-Baameiro N, Camino T, Vazquez-Durán A, et al. Intra and inter-organ communication through extracellular vesicles in obesity: Functional role of obesesomes and steatosomes[J]. J Transl Med, 2025, 23( 1): 207. DOI: 10.1186/s12967-024-06024-7.
[38]	Blandin A, Amosse J, Froger J, et al. Extracellular vesicles are carriers of adiponectin with insulin-sensitizing and anti-inflammatory properties[J]. Cell Rep, 2023, 42( 8): 112866. DOI: 10.1016/j.celrep.2023.112866.
[39]	Lin A H, He W J. LINC01705 derived from adipocyte exosomes regulates hepatocyte lipid accumulation via an miR-552-3p/LXR axis[J]. J Diabetes Investig, 2023, 14( 10): 1160- 1171. DOI: 10.1111/jdi.14050.
[40]	Rong B H, Feng R N, Liu C L, et al. Reduced delivery of epididymal adipocyte-derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice[J]. J Pineal Res, 2019, 66( 4): e12561. DOI: 10.1111/jpi.12561.
[41]	Thomou T, Mori M A, Dreyfuss J M, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues[J]. Nature, 2017, 542( 7642): 450- 455. DOI: 10.1038/nature21365.
[42]	Xu J H, Cui L, Wang J Q, et al. Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice[J]. Nat Commun, 2023, 14: 5480. DOI: 10.1038/s41467-023-41160-6.
[43]	Kariba Y, Yoshizawa T, Sato Y, et al. Brown adipocyte-derived exosomal miR-132-3p suppress hepatic Srebf1 expression and thereby attenuate expression of lipogenic genes[J]. Biochem Biophys Res Commun, 2020, 530( 3): 500- 507. DOI: 10.1016/j.bbrc.2020.05.090.
[44]	Yang L J, Tang Q K, Wang L, et al. The brown fat-enriched exosomal miR-206-3p attenuates hepatic lipogenesis by decreasing pentose phosphate pathway[J]. Life Metab, 2025, 4( 6): loaf028. DOI: 10.1093/lifemeta/loaf028.
[45]	Zheng Shasha. The mechanisms of brown adipocyte-derived miRNAs reprogramming energy metabolism in other tissues[D]. Nanjing: Nanjing University, 2019. DOI: 10.27235/d.cnki.gnjiu.2019.001298. 郑莎莎. 棕色脂肪分泌miRNA跨组织调节代谢稳态的机制研究[D]. 南京: 南京大学, 2019. DOI: 10.27235/d.cnki.gnjiu.2019.001298.
[46]	Ying W, Riopel M, Bandyopadhyay G, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity[J]. Cell, 2017, 171( 2): 372- 384.e12. DOI: 10.1016/j.cell.2017.08.035.
[47]	Haraszti R A, Didiot M C, Sapp E, et al. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources[J]. J Extracell Vesicles, 2016, 5( 1): 32570. DOI: 10.3402/jev.v5.32570.
[48]	van de Wakker S I, Meijers F M, Sluijter J P G, et al. Extracellular vesicle heterogeneity and its impact for regenerative medicine applications[J]. Pharmacol Rev, 2023, 75( 5): 1043- 1061. DOI: 10.1124/pharmrev.123.000841.
[49]	Wang W H, Qiao S Y, Kong X H, et al. The role of exosomes in immunopathology and potential therapeutic implications[J]. Cell Mol Immunol, 2025, 22( 9): 975- 995. DOI: 10.1038/s41423-025-01323-5.
[50]	Li B, Sun J, Zheng Y Y, et al. Letter: Increased prevalence of visceral obesity in nonresponder patients with primary biliary cholangitis based on computed tomography[J]. Aliment Pharmacol Ther, 2025, 61( 3): 589- 590. DOI: 10.1111/apt.18440.
[51]	Liu Y, Tan J, Ou S Y, et al. Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis[J]. J Physiol Biochem, 2019, 75( 3): 391- 401. DOI: 10.1007/s13105-019-00692-6.
[52]	Wang C, Zheng Z, Wu C, et al. Adipose-Derived Exosomes: mediators of crosstalk between Adipose tissue and cancer[J]. Cancer Biol Ther, 2025, 26( 1): 2547564. DOI: 10.1080/15384047.2025.2547564.
[53]	Zhao H, Chen X Y, Hu G Y, et al. Small extracellular vesicles from brown adipose tissue mediate exercise cardioprotection[J]. Circ Res, 2022, 130( 10): 1490- 1506. DOI: 10.1161/CIRCRESAHA.121.320458.
[54]	Lin J R, Ding L L, Xu L, et al. Brown adipocyte ADRB3 mediates cardioprotection via suppressing exosomal iNOS[J]. Circ Res, 2022, 131( 2): 133- 147. DOI: 10.1161/CIRCRESAHA.121.320470.
[55]	Rosina M, Ceci V, Turchi R, et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue[J]. Cell Metab, 2022, 34( 4): 533- 548.e12. DOI: 10.1016/j.cmet.2022.02.016.
[56]	Mo W H, Peng Y K, Zheng Y Y, et al. Extracellular vesicle-mediated bidirectional communication between the liver and other organs: Mechanistic exploration and prospects for clinical applications[J]. J Nanobiotechnol, 2025, 23( 1): 190. DOI: 10.1186/s12951-025-03259-4.