School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People's Republic of China.
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
Int J Nanomedicine. 2024 Sep 30;19:10023-10043. doi: 10.2147/IJN.S478589. eCollection 2024.
Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM.
The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells.
TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α).
We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid β-oxidation and glycolysis.
非酒精性脂肪性肝病（NAFLD）是一种严重的全球性健康负担，与胰岛素抵抗、肥胖和 2 型糖尿病（T2DM）密切相关。尽管 T2DM 患者的肝脂肪变性程度严重，但尚无专门用于临床治疗该疾病的药物。陈皮是一种受欢迎的功能性食品，据报道具有降血糖和降血脂的潜力。在这项研究中，我们研究了源自陈皮的外泌体样纳米囊泡（TNVs）对与 T2DM 相关的肝脂肪毒性的影响。
通过陈皮水提物的差速离心制备 TNVs，并通过透射电子显微镜（TEM）、纳米颗粒跟踪分析（NTA）和 LC-MS/MS 对其化学性质进行了表征。通过生化测定、RT-PCR、16S rRNA 测序、GC/MS、UHPLC-MS/MS、小动物体内成像分析和 HE 染色研究了 TNVs 的降血糖和降血脂作用。随后，在 3T3-L1 和 AML-12 细胞上研究了 TNVs 对脂质积累和糖酵解的影响。
TNVs 显著抑制胰岛素抵抗，减少肝脂质积累，促进肠道黏膜修复，挽救肠道微生物群失调，调节结肠短链脂肪酸和肝胆汁酸代谢，改善高脂高糖饮食诱导的 T2DM 小鼠的葡萄糖和脂质代谢。此外，TNVs 恢复了葡萄糖和脂质代谢关键基因（ACC、AMPK、CD36、LXRα、PPAR-γ、SREBP-1）的表达，同时激活了糖酵解相关基因（G6Pase、GLUT2、PCK1、PEPCK）的表达。进一步的细胞机制研究表明，TNVs 通过调节葡萄糖和脂质代谢相关基因（UCP1、FGFR4、PRDM16、PGC-1α、Tmem26、CPT1、CPT2 和 PPAR-α）减少 3T3-L1 和 AML-12 细胞中的脂质积累。
我们首次证明，TNVs 通过激活与脂肪酸β氧化和糖酵解相关的基因表达，显著改善葡萄糖和脂质代谢。
