Lu Fengyuan, Li En, Gao Yifeng, Zhang Yan, Kong Lijuan, Yang Xiaoyu
The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Diabetes Obes Metab. 2025 Apr;27(4):2096-2109. doi: 10.1111/dom.16202. Epub 2025 Jan 20.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear.
We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism.
We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C.
Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）主要由肝脏分泌，在脂质代谢紊乱中起关键作用。钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）可通过多种途径调节脂质代谢，包括减少内脏脂肪堆积、调节血清脂蛋白水平和减轻肝脂肪变性。然而，具体的调节机制仍不清楚。
我们在体内和体外建立了糖脂代谢紊乱模型，并探讨了达格列净调节肝脏脂质代谢的机制。
我们发现，SGLT2i达格列净显著降低了高脂饮食（HFD）喂养小鼠的血清PCSK9、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）水平，同时还改善了肝脂肪变性。体外研究证实，达格列净增加了HepG2细胞中低密度脂蛋白受体（LDLR）的表达，增强了它们摄取LDL-C的能力。
进一步的机制研究表明，肝细胞核因子-1α（HNF1α）/PCSK9/LDLR信号通路可能参与达格列净对脂质代谢稳态的调节。
