Department of Cardiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
Hepatology. 2021 Oct;74(4):2154-2169. doi: 10.1002/hep.31856. Epub 2021 Aug 30.
Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon-like peptide 1 (GLP-1)-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide.
Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high-fat diet (HFD)-fed mice and compared with the effects of the dipeptidyl-peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r mice and liver-specific FGF21-knockout (lFgf21-KO) mice. In wild-type mouse liver that underwent RNA sequencing and quantitative reverse-transcription PCR, we observed liraglutide-stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD-induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated mice but was not observed in sitagliptin-treated mice. In HFD-fed Glp1r mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice undergoing dietary challenge, the body-weight-gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced.
We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP-1-based drugs in NAFLD.
几项研究表明，胰高血糖素样肽 1（GLP-1）类糖尿病药物可以刺激肝成纤维细胞生长因子 21（FGF21）的表达。由于 GLP-1 受体（GLP-1R）不太可能在肝细胞中表达，我们旨在比较这种在小鼠和小鼠原代肝细胞（MPHs）中的刺激作用，确定 GLP-1R 的参与情况，并阐明 FGF21 是否介导了利拉鲁肽这种 GLP-1R 激动剂的某些功能。
在接受每日利拉鲁肽注射 3 天的小鼠或直接接受利拉鲁肽处理的小鼠原代肝细胞（MPHs）中评估肝 FGF21 的表达。然后，在高脂肪饮食（HFD）喂养的小鼠中评估利拉鲁肽对代谢改善和 FGF21 表达的影响，并与二肽基肽酶 4 抑制剂西他列汀的作用进行比较。还在 Glp1r 小鼠和肝脏特异性 FGF21 敲除（lFgf21-KO）小鼠中进行了动物研究。在接受 RNA 测序和定量逆转录 PCR 的野生型小鼠肝中，我们观察到利拉鲁肽刺激肝 Fgf21 的表达，而没有观察到 Glp1r 的表达。在 MPHs 中，利拉鲁肽没有刺激 Fgf21 的表达。在 HFD 诱导肥胖的小鼠中，利拉鲁肽或西他列汀治疗降低了血浆甘油三酯水平，但其降低体重增加的作用不同。重要的是，在利拉鲁肽治疗的小鼠中观察到肝 FGF21 表达增加，但在西他列汀治疗的小鼠中未观察到。在 HFD 喂养的 Glp1r 小鼠中，利拉鲁肽没有显示出有益的作用，也不能刺激 Fgf21 的表达。在接受饮食挑战的 lFgf21-KO 小鼠中，利拉鲁肽的体重增加抑制和脂质稳态作用丧失或显著降低。
我们建议，利拉鲁肽刺激肝 Fgf21 表达可能需要 GLP-1R 在肝外器官中表达。重要的是，我们揭示了肝 FGF21 是利拉鲁肽降低体重和改善肝脂质稳态的必需条件。这些观察结果增进了我们对 GLP-1 类药物在非酒精性脂肪性肝病中的作用机制的理解。
