FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.
FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.
复制标题
FGF21缺失通过加重心脏脂质积累而加剧糖尿病心肌病。
DOI：
10.1111/jcmm.12530
复制
发表时间：
2015-07
影响因子：
5.3
通讯作者：
Tan Y
中科院分区：
文献类型：
--
作者：
Yan X;Chen J;Zhang C;Zhou S;Zhang Z;Chen J;Feng W;Li X;Tan Y
成纤维细胞生长因子 21 (FGF21) 在能量稳态中发挥重要作用。本文利用 FGF21 敲除 (FGF21KO) 糖尿病小鼠研究了 FGF21 对糖尿病心肌病 (DCM) 发生和进展的影响这一尚未解决的问题。通过链脲佐菌素在 FGF21KO 和 C57BL/6J 野生型 (WT) 小鼠中诱导 1 型糖尿病。在糖尿病发病后 1、2 和 4 个月，与对照组相比，WT 糖尿病小鼠的血浆 FGF21 水平显着降低。 FGF21KO和WT糖尿病小鼠的血糖和甘油三酯水平没有显着差异。与WT糖尿病小鼠相比，FGF21KO糖尿病小鼠表现出更早、更严重的心脏功能障碍、重构和氧化应激，以及心脏脂质积累更大的增加。蛋白质印迹显示，与 WT 糖尿病小鼠相比，FGF21KO 糖尿病小鼠心脏中脂质积累增加，伴随着核因子（红细胞衍生 2）样 2 (Nrf2) 及其靶蛋白 CD36 表达的进一步增加，以及 AMP 激活蛋白激酶的磷酸化以及己糖激酶 II 和过氧化物酶体增殖物激活受体 γ 共激活剂 1α 表达的降低。我们的结果表明，FGF21 缺失加剧的心脏脂质积累可能是由心脏 Nrf2 驱动的 CD36 上调介导的，这可能导致心脏氧化应激和重塑增加，以及 DCM 的最终发展。这些发现表明FGF21可能是治疗DCM的治疗靶点。
Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21’s effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1α in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.