Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Key Laboratory of Hubei Province for Digestive Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Key Laboratory of Hubei Province for Digestive Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Biochem Biophys Res Commun. 2021 Apr 2;547:131-138. doi: 10.1016/j.bbrc.2021.02.039. Epub 2021 Feb 17.
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide and an urgent target for clinical intervention. Notch1 signaling pathway activity was found to be related to the severity of NAFLD, but the specific mechanism is not precise. Here, we investigated the potential mechanisms of Notch1 signaling in the development of NAFLD. Firstly, we found that Notch1 signaling is activated in free fatty acids-treated HepG2 cells accompanied by lipid accumulation, apoptosis, oxidative stress, and mitochondrial damage, which could be alleviated by Notch1 inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). In the meantime, we found that administration of DAPT activated the autophagy pathway in NAFLD. Furthermore, the use of autophagy inhibitor chloroquine reversed the DAPT-mediated protective effect in NAFLD. All our results uncover a vital role of Notch1 in hepatocyte injury and metabolism of NAFLD, giving rise to a new sight for NAFLD treatment by regulation of Notch signaling and autophagy pathway.
非酒精性脂肪性肝病（NAFLD）已成为全球最常见的慢性肝病病因，也是临床干预的迫切目标。研究发现 Notch1 信号通路的活性与 NAFLD 的严重程度有关，但具体机制尚不清楚。在这里，我们研究了 Notch1 信号通路在 NAFLD 发展中的潜在机制。首先，我们发现游离脂肪酸处理的 HepG2 细胞中 Notch1 信号通路被激活，伴随着脂质积累、细胞凋亡、氧化应激和线粒体损伤，而 Notch1 抑制剂 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-S-苯甘氨酸叔丁酯（DAPT）可减轻这些损伤。同时，我们发现 DAPT 可激活 NAFLD 中的自噬途径。此外，使用自噬抑制剂氯喹可逆转 DAPT 介导的 NAFLD 保护作用。我们的所有结果揭示了 Notch1 在肝细胞损伤和 NAFLD 代谢中的重要作用，为通过调节 Notch 信号通路和自噬途径治疗 NAFLD 提供了新的思路。
