Yang Ni, Pang Yue-Shan, Zheng Yali, Gong Yan-Ju, Ding Wei-Jun
Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan Province, China.
Mol Med. 2025 Jan 26;31(1):26. doi: 10.1186/s10020-025-01072-1.
The incidence of obesity is increasing annually worldwide. A high-fat diet (HFD) causes intestinal barrier damage, but effective interventions are currently unavailable. Our previous work demonstrated the therapeutic effect of nobiletin on obese mice; thus, we hypothesized that nobiletin could reverse HFD-induced damage to the intestinal barrier. Male C57BL/6 J mice were orally administered nobiletin for 14 d. After identification, the obese mice were equally divided into three groups: the HFD group, the low-dose (NOL, 100 mg/kg/d) group and the high-dose nobiletin (NOH, 200 mg/kg/d) group. A normal control group (CON) was also included. Hematoxylin and eosin (HE) staining and immunofluorescence were used to observe the intestinal barrier. RT-qPCR was used to determine the transcriptomic levels of genes involved in intestinal barrier integrity and lipid metabolism. The results revealed that intestinal tight proteins, including ZO-1 and Occludin, were significantly reduced in HFD-fed mice but markedly restored after nobiletin intervention, particularly in NOH mice. Improvements in the intestinal barrier and lipid metabolism associated with major histocompatibility complex class II (MHC-II) and relevant elements were revealed after nobiletin intervention. Enrichment analysis revealed that MHC-II plays an important role in the restoration of the intestinal barrier. Taken together, nobiletin restored intestinal barrier integrity and lipid metabolism by regulating MHC-II expression.
全球肥胖症的发病率正逐年上升。高脂饮食（HFD）会导致肠道屏障受损，但目前尚无有效的干预措施。我们之前的研究表明了橙皮素对肥胖小鼠具有治疗作用；因此，我们推测橙皮素可以逆转高脂饮食引起的肠道屏障损伤。对雄性C57BL/6 J小鼠口服橙皮素14天。鉴定后，将肥胖小鼠平均分为三组：高脂饮食组、低剂量（NOL，100毫克/千克/天）组和高剂量橙皮素（NOH，200毫克/千克/天）组。还设立了一个正常对照组（CON）。采用苏木精-伊红（HE）染色和免疫荧光法观察肠道屏障。采用RT-qPCR法测定参与肠道屏障完整性和脂质代谢的基因的转录水平。结果显示，高脂饮食喂养的小鼠中，包括紧密连接蛋白1（ZO-1）和闭合蛋白在内的肠道紧密蛋白显著减少，但在橙皮素干预后明显恢复，尤其是在NOH组小鼠中。橙皮素干预后，发现与主要组织相容性复合体II类（MHC-II）及相关元件有关的肠道屏障和脂质代谢得到改善。富集分析表明，MHC-II在肠道屏障的恢复中起重要作用。综上所述，橙皮素通过调节MHC-II的表达恢复了肠道屏障的完整性和脂质代谢。
