Zhu Shenglong, Wu Yunzhou, Ye Xianlong, Ma Lei, Qi Jianying, Yu Dan, Wei Yuquan, Lin Guangxiao, Ren Guiping, Li Deshan
School of Life Science, Northeast Agricultural University, Harbin, China.
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.
Mol Cell Biochem. 2016 Sep;420(1-2):107-19. doi: 10.1007/s11010-016-2774-2. Epub 2016 Jul 19.
The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P < 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy.
本研究旨在评估成纤维细胞生长因子21（FGF21）在非酒精性脂肪性肝病（NAFLD）中的作用，并试图确定其治疗效果是否通过诱导自噬实现。在本研究中，分别用赋形剂、非诺贝特和重组小鼠FGF21处理谷氨酸钠（MSG）诱导的肥胖小鼠或正常瘦小鼠。治疗5周后，监测并分析包括体重、血糖和血脂水平、肝脏和脂肪基因表达水平在内的代谢参数。此外，用赋形剂或重组小鼠FGF21处理脂肪负荷的HepG2细胞。通过蛋白质免疫印迹法、实时聚合酶链反应和透射电子显微镜（TEM）检测与自噬相关的蛋白质表达水平。通过激光共聚焦显微镜和蛋白质免疫印迹法监测自噬通量。结果显示，FGF21显著降低了MSG模型小鼠的体重（P<0.01）和血清甘油三酯水平，改善了胰岛素敏感性，并逆转了肝脏脂肪变性。此外，FGF21显著增加了MSG小鼠和脂肪负荷的HepG2细胞中几种与自噬相关的蛋白质的表达，如微管相关蛋白1轻链3、Bcl-2相互作用的肌球蛋白样卷曲螺旋蛋白-1（Beclin-1）和自噬相关基因5。此外，TEM证据显示，用FGF21处理的模型细胞中自噬体和溶酶体数量增加。体外实验结果还表明，FGF21显著增加了自噬通量。综上所述，FGF21通过诱导自噬在体外和体内纠正了NAFLD的多个代谢参数。
