Jin Leigang, Lin Zhuofeng, Xu Aimin
State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong.
Department of Pharmacology and Pharmacy, the University of Hong Kong, Hong Kong.
Diabetes Metab J. 2016 Feb;40(1):22-31. doi: 10.4093/dmj.2016.40.1.22.
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.
成纤维细胞生长因子21（FGF21）是一种对能量代谢和胰岛素敏感性具有多效性作用的代谢激素。除了其抗肥胖和抗糖尿病活性外，FGF21还具有抗动脉粥样硬化的保护作用。动脉粥样硬化患者、糖尿病大血管和微血管并发症患者的循环FGF21水平升高，这可能是由于代偿性上调所致。在载脂蛋白E缺乏的小鼠中，FGF21基因缺失会加剧动脉粥样硬化斑块的形成，但补充重组FGF21后则会减轻。然而，血管并非FGF21的直接靶点，FGF21的抗动脉粥样硬化活性归因于其在脂肪组织和肝脏中的作用。在脂肪细胞中，FGF21促进脂联素的分泌，脂联素进而直接作用于血管，以减少内皮功能障碍、抑制平滑肌细胞增殖并阻止巨噬细胞转化为泡沫细胞。此外，FGF21通过抑制肝细胞中的转录因子固醇调节元件结合蛋白2来抑制胆固醇生物合成并减轻高胆固醇血症。在肥胖和糖尿病患者的1b期临床试验中也观察到了FGF21对脂联素升高和高胆固醇血症降低的影响。因此，FGF21通过微调肝脏、大脑、脂肪组织和血管之间的器官间相互作用来发挥其抗动脉粥样硬化的保护作用。
