Su Shan, Liu Xiaohong, Zhu Min, Liu Wen, Liu Jingyi, Yuan Yujia, Fu Fudong, Rao Zhiyong, Liu Jingping, Lu Yanrong, Chen Younan
Department of Clinical Nutrition and National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610000, P. R. China.
J Agric Food Chem. 2025 Jan 8;73(1):521-540. doi: 10.1021/acs.jafc.4c08669. Epub 2024 Dec 16.
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic lipid deposition, is one of the most prevalent chronic metabolic disorders globally, and its pharmaceutical treatments are still limited. Excessive lipid accumulation triggers endoplasmic reticulum (ER) stress and autophagy flux dysfunction, which are important mechanisms for NAFLD. Trehalose (Tre), a natural disaccharide, has been identified to reduce hepatic steatosis and glucose intolerance. However, its underlying mechanisms for NAFLD remain unclear. In this study, a high-fat-diet (HFD)-induced mouse NAFLD model and a saturated fatty acid palmitic acid (PA)-stimulated cell model were constructed. The results indicated that Tre supplementation ameliorated hepatocyte lipid deposition , as well as hepatic steatosis and hyperlipidemia . Mechanistically, Tre alleviated both autophagy flux dysfunction and endoplasmic reticulum (ER) stress. Under the stimulation of HFD or PA, Tre remarkably increased the expression and nucleic translocation of the lysosomal master protein transcription factor EB (TFEB), while decreasing the accumulation of p62 and also decreasing the ER stress markers (inositol-requiring enzyme 1 (IRE1α), XBP-1, CHOP, and BIP). Similar results were observed in an ER stressor tunicamycin (TM)-induced and models. In addition, the transcriptomic analysis of NAFLD patients revealed significant differences in ER stress-related and autophagy-related biomarkers, including TFEB, ATG7, IRE1α, and CHOP. Molecular docking results demonstrated a strong affinity between Tre and both IRE1α and TFEB. Overall, Tre protected hepatocytes from lipotoxicity-related ER stress and autophagy dysfunction, and its regulatory effect on the IRE1α-TFEB signaling pathway may be a critical mechanism. These findings suggest that Tre, as a bioactive substance with significant medicinal potential, holds considerable promise for drug development and clinical application in treating NAFLD.
非酒精性脂肪性肝病（NAFLD）以肝脏脂质沉积为特征，是全球最普遍的慢性代谢紊乱疾病之一，其药物治疗仍然有限。过量的脂质积累引发内质网（ER）应激和自噬通量功能障碍，这是NAFLD的重要发病机制。海藻糖（Tre）是一种天然二糖，已被证实可减轻肝脏脂肪变性和葡萄糖不耐受。然而，其治疗NAFLD的潜在机制仍不清楚。在本研究中，构建了高脂饮食（HFD）诱导的小鼠NAFLD模型和饱和脂肪酸棕榈酸（PA）刺激的细胞模型。结果表明，补充Tre可改善肝细胞脂质沉积，以及肝脏脂肪变性和高脂血症。机制上，Tre减轻了自噬通量功能障碍和内质网（ER）应激。在HFD或PA刺激下，Tre显著增加了溶酶体主要蛋白转录因子EB（TFEB）的表达和核转位，同时减少了p62的积累，并降低了ER应激标志物（肌醇需求酶1（IRE1α）、XBP-1、CHOP和BIP）。在内质网应激诱导剂衣霉素（TM）诱导的模型中也观察到了类似结果。此外，对NAFLD患者的转录组分析显示，内质网应激相关和自噬相关生物标志物（包括TFEB、ATG7、IRElα和CHOP）存在显著差异。分子对接结果表明，Tre与IRE1α和TFEB均具有很强的亲和力。总体而言，Tre保护肝细胞免受脂毒性相关的内质网应激和自噬功能障碍，其对IRE1α-TFEB信号通路的调节作用可能是关键机制。这些发现表明，Tre作为一种具有显著药用潜力的生物活性物质，在治疗NAFLD的药物开发和临床应用方面具有广阔前景。
