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作者

Jing-Jing Han, Jing Li, Dong-Hui Huang

作者单位

Affiliations ¹ Department of Endocrinology, The Second Affiliated Hospital of Shandong First Medical University, Taishan Street Road No.366, Tai'an, 271000, Shandong, China. ² Department of Pediatric, The Secondary TCM Hospital of Tai'an City, Lingshan Street No.265, Tai'an, 271000, Shandong, China. ³ Department of Endocrinology, The Second Affiliated Hospital of Shandong First Medical University, Taishan Street Road No.366, Tai'an, 271000, Shandong, China. huangdonghui223@16 com.

刊名

Tissue engineering and regenerative medicine

年份

2024

ISSN

2212-5469

关键词

ABHD6 Circ-Tulp4 Diabetes mellitus with nonalcoholic fatty liver disease Extracellular vesicles HNRNPC Pyroptosis.

摘要

Background: Diabetes mellitus with nonalcoholic fatty liver disease represents a complex metabolic syndrome with significant clinical challenges. This study explores the therapeutic potential and underlying mechanisms of umbilical cord-derived mesenchymal stem cells -derived extracellular vesicles in DM-NAFLD. Methods: UCMSCs-EVs were isolated and characterized. DM-NAFLD mouse model was developed through high-energy diet and streptozotocin injection. Additionally, primary mouse hepatocytes wer...更多

Background: Diabetes mellitus with nonalcoholic fatty liver disease represents a complex metabolic syndrome with significant clinical challenges. This study explores the therapeutic potential and underlying mechanisms of umbilical cord-derived mesenchymal stem cells -derived extracellular vesicles in DM-NAFLD. Methods: UCMSCs-EVs were isolated and characterized. DM-NAFLD mouse model was developed through high-energy diet and streptozotocin injection. Additionally, primary mouse hepatocytes were exposed to high glucose to simulate cellular conditions. Hepatic tissue damage, body weight changes, lipid levels, glucose and insulin homeostasis, and hepatic lipid accumulation were evaluated. The interaction between UCMSCs-EVs and hepatocytes was assessed, focusing on the localization and function of circ-Tulp4. The study also investigated the expression of circularRNA TUB-like protein 4 , heterogeneous nuclear ribonucleoprotein C , abhydrolase domain containing 6 , cleaved Caspase-1, NLR family pyrin domain containing 3 and cleaved N-terminal gasdermin D . The binding of circ-Tulp4 to lysine demethylase 6B and the subsequent epigenetic regulation of ABHD6 by H3K27me3 were analyzed. Results: Circ-Tulp4 was reduced, while HNRNPC and ABHD6 were elevated in DM-NAFLD models. UCMSCs-EVs attenuated hepatic steatosis and inhibited the NLRP3/cleaved Caspase-1/GSDMD-N pathway. EVs delivered circ-Tulp4 into hepatocytes, thereby restoring circ-Tulp4 expression. Elevated circ-Tulp4 enhanced the recruitment of H3K27me3 to the HNRNPC promoter through interaction with KDM6B, thus suppressing HNRNPC and ABHD6. Overexpression of HNRNPC or ABHD6 counteracted the protective effects of UCMSCs-EVs, exacerbating pyroptosis and hepatic steatosis in DM-NAFLD. Conclusion: UCMSCs-EVs deliver circ-Tulp4 into hepatocytes, where circ-Tulp4 inhibits the HNRNPC/ABHD6 axis, thereby reducing pyroptosis and alleviating DM-NAFLD. These findings provide a novel therapeutic avenue for targeting DM-NAFLD through modulation of cell pyroptosis.收起

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