Abstract
Adipose tissue dysfunction drives hepatic lipid overload in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the involvement of adipose tissue-derived small extracellular vesicles (sEVs) remains unclear. Herein, we showed that transplanting adipose tissue from high‑fat diet (HFD)-fed male mice exacerbated insulin resistance and hepatic steatosis in lean recipients. Adipose‑specific Sirt3 overexpression (Sirt3AKI) alleviated insulin resistance and liver steatosis in HFD-fed male mice, whereas adipose‑specific Sirt3 knockdown aggravated these phenotypes. Moreover, adipose sEV miRNAs regulated hepatic lipid metabolism in Sirt3AKI male mice. MicroRNA sequencing identified miR-30a-3p was increased in the circulating sEVs from HFD-fed male mice, while decreased in sEVs from Sirt3OE adipocytes and Sirt3AKI male mice. Mechanistically, miR‑30a‑3p promoted hepatic steatosis by targeting Becn1; this process was suppressed when Sirt3 downregulated miR‑30a‑3p transcription via deacetylation of H3K56. These findings highlight the critical role of adipose sEV microRNAs in driving hepatocyte lipotoxicity, and suggest miR-30a-3p inhibition as a promising MASLD therapy.
Data availability
The source data file for plots and western blots are provided with this paper. Plasmids, lentiviral constructs and cell lines described in this study are available upon request from the corresponding author. The raw human samples and data are not available due to patient privacy issues and compliance with the HIPAA (Health Insurance Portability and Accountability Act). CHIP sequencing data have been deposited in the NCBI GEO database under the accession number GSE307665. miRNA-sequencing data have been deposited in the NCBI GEO database under the accession number GSE325068 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325068). Some data of CHIP sequencing are also provided in Additional Supplementary Files. Source data are provided with this paper. All other data generated in this study are provided in the Article, Supplementary information, or Source Data file. Source data are provided with this paper.
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Acknowledgements
Financial support by National Natural Science Foundation of China (82100623 and 32360174 to T.Z., 82170743 to B.G., 82073715 to L.L., 82404648 to K.L.), Science and Technology Development Fund, Macao SAR (File No. FDCT 0057/2025/RIB2 to L.L.), Guizhou Provincial Science and Technology Projects (ZK [2024]113 to T.Z. and Z.K. [2022]378 to M.J.S.), Scientific and Technological Innovation Platform Research Project of Guizhou Province (CXPTXM [2025] 009), Guizhou Science and Technology Department (grant numbers CXPTXM [2025]010/[2025]021/KXJZ[2025]014), China Postdoctoral Science Foundation (2022M720040), Excellent Young Talents Plan of Guizhou Medical University (2022108) and Guizhou Provincial Major Scientific and Technological Program ([2024]015) are gratefully acknowledged.
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T.Z. contributed to investigation, data curation, formal analysis, visualization, and wrote the original draft. T.Z., L.H., D.C., and Y.C. contributed to investigation, methodology, formal analysis, and review and editing. T.Z. and L.L. conceptualized the study. K.L. was responsible for investigation, validation, resources, and review and editing. F.Z. and R.L. contributed to data curation. Y.Z., Y.W., and M.J.S. contributed to writing-review and editing. T.Z., L.L., and B.G. supervised the study, acquired funding, conceptualized the study, and contributed to writing-review and editing.
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Zhang, T., Hu, L., Chen, D. et al. Adipocyte small extracellular vesicle-derived microRNA-30a-3p exacerbates hepatic steatosis in high fat diet-fed male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71731-2
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DOI: https://doi.org/10.1038/s41467-026-71731-2
