Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice.
Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice.
复制标题
DOI：
10.1161/circulationaha.115.015308
复制
发表时间：
2015-05-26
期刊：
影响因子：
37.8
通讯作者：
Xu A
中科院分区：
文献类型：
--
作者：
Lin Z;Pan X;Wu F;Ye D;Zhang Y;Wang Y;Jin L;Lian Q;Huang Y;Ding H;Triggle C;Wang K;Li X;Xu A
补充数字内容可在正文中找到。成纤维细胞生长因子21(FGF21)是一种对糖脂代谢和胰岛素敏感性具有多效性的代谢激素。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脂和胰岛素增敏。然而，FGF21在心血管系统中的作用仍然难以捉摸。通过评价FGF21缺失和重组FGF21对载脂蛋白E−/−小鼠动脉粥样硬化的影响，探讨FGF21在动脉粥样硬化中的作用。FGF21缺乏导致载脂蛋白E−/−小鼠动脉粥样硬化斑块形成和过早死亡的显著加剧，并伴有低脂联素血症和严重的高胆固醇血症。补充成纤维细胞生长因子21通过两个独立的机制保护载脂蛋白E−/−小鼠的动脉粥样硬化：诱导脂肪细胞产生脂联素，脂联素反过来作用于血管，抑制新生内膜形成和巨噬细胞炎症；抑制转录因子固醇调节元件结合蛋白-2的肝脏表达，从而减少胆固醇合成，缓解高胆固醇血症。脂联素慢性治疗可部分逆转动脉粥样硬化，但对FGF21缺陷的载脂蛋白E−/−小鼠的高胆固醇血症无明显影响。相比之下，FGF21的降胆固醇作用被肝脏表达的固醇调节元件结合蛋白-2所抵消。FGF21通过微调肝脏、脂肪组织和血管之间的多器官串扰来预防动脉粥样硬化。
Supplemental Digital Content is available in the text. 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.