Lin Zhuofeng, Pan Xuebo, Wu Fan, Ye Dewei, Zhang Yi, Wang Yu, Jin Leigang, Lian Qizhou, Huang Yu, Ding Hong, Triggle Chris, Wang Kai, Li Xiaokun, Xu Aimin
From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
Circulation. 2015 May 26;131(21):1861-71. doi: 10.1161/CIRCULATIONAHA.115.015308. Epub 2015 Mar 20.
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive.
The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.
FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
成纤维细胞生长因子21（FGF21）是一种对葡萄糖和脂质代谢以及胰岛素敏感性具有多效性作用的代谢激素。它是过氧化物酶体增殖物激活受体α和γ的关键下游靶点，这两种受体的激动剂分别用于降低血脂和提高胰岛素敏感性。然而，FGF21在心血管系统中的作用仍不明确。
通过评估FGF21缺乏以及用重组FGF21补充对载脂蛋白E基因敲除（apoE-/-）小鼠的影响，研究FGF21在动脉粥样硬化中的作用。FGF21缺乏导致apoE-/-小鼠动脉粥样硬化斑块形成显著加剧和过早死亡，同时伴有低脂联素血症和严重的高胆固醇血症。补充FGF21通过两种独立机制预防apoE-/-小鼠的动脉粥样硬化，诱导脂肪细胞产生脂联素，脂联素进而作用于血管以抑制内膜增生和巨噬细胞炎症，并抑制转录因子固醇调节元件结合蛋白2的肝脏表达，从而导致胆固醇合成减少和高胆固醇血症减轻。在FGF21缺乏的apoE-/-小鼠中，长期用脂联素治疗可部分逆转动脉粥样硬化，而对高胆固醇血症无明显影响。相比之下，FGF21的降胆固醇作用可被固醇调节元件结合蛋白2的肝脏表达消除。
FGF21通过微调肝脏、脂肪组织和血管之间的多器官相互作用来预防动脉粥样硬化。
