Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart.
Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart.
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成纤维细胞生长因子 21 通过 AMPK 介导的心脏抗氧化和降脂作用预防糖尿病心肌病
DOI：
10.1038/s41419-018-0307-5
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Yang H;Feng A;Lin S;Yu L;Lin X;Yan X;Lu X;Zhang C
我们之前的研究表明，外源性和内源性FGF21都能抑制1型糖尿病早期的心脏凋亡。本研究探讨FGF21是否对2型糖尿病引起的心肌病具有预防作用。高脂肪饮食/链脲佐菌素诱导的2型糖尿病在野生型（WT）和FGF21敲除（FGF21- ko）小鼠中建立，随后用FGF21治疗4个月。糖尿病性心肌病（DCM）的诊断是通过明显的心功能障碍、重塑和心脏脂质积累，并伴有细胞凋亡、炎症和氧化应激的增加，这些在FGF21-KO小鼠中加重。然而，给药FGF21可以预防上述心脏损伤。进一步的研究表明，FGF21的代谢调节作用并不足够，这有助于FGF21在糖尿病条件下诱导显著的心脏保护作用。因此，必须存在其他保护机制。HG/Pal对初生或成年小鼠心肌细胞的体内心脏损伤模拟，FGF21可抑制HG/Pal对心肌细胞的损伤。敲低AMPKα1/2、AKT2或NRF2及其sirna表明，FGF21通过上调ampk - AKT2 - NRF2介导的抗氧化途径部分保护心肌细胞免受HG/Pal的影响。此外，AMPK的下调通过抑制ACC-CPT-1途径抑制脂肪酸β-氧化。脂肪酸β-氧化抑制部分阻断了fgf21诱导的心肌细胞保护作用。此外，体外和体内研究表明，fgf21诱导的对2型糖尿病的心脏保护主要归因于脂肪毒性而不是葡萄糖毒性。这些结果表明，FGF21通过激活ampk - akt2 - nrf2介导的抗氧化途径和ampk - acc - cpt -1介导的心脏降脂作用，在生理和药理学上具有预防2型糖尿病脂肪中毒引起的心肌病的功能。
Our previous studies showed that both exogenous and endogenous FGF21 inhibited cardiac apoptosis at the early stage of type 1 diabetes. Whether FGF21 induces preventive effect on type 2 diabetes-induced cardiomyopathy was investigated in the present study. High-fat-diet/streptozotocin-induced type 2 diabetes was established in both wild-type (WT) and FGF21-knockout (FGF21-KO) mice followed by treating with FGF21 for 4 months. Diabetic cardiomyopathy (DCM) was diagnosed by significant cardiac dysfunction, remodeling, and cardiac lipid accumulation associated with increased apoptosis, inflammation, and oxidative stress, which was aggravated in FGF21-KO mice. However, the cardiac damage above was prevented by administration of FGF21. Further studies demonstrated that the metabolic regulating effect of FGF21 is not enough, contributing to FGF21-induced significant cardiac protection under diabetic conditions. Therefore, other protective mechanisms must exist. The in vivo cardiac damage was mimicked in primary neonatal or adult mouse cardiomyocytes treated with HG/Pal, which was inhibited by FGF21 treatment. Knockdown of AMPKα1/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG/Pal partially via upregulating AMPK–AKT2–NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid β-oxidation via inhibition of ACC–CPT-1 pathway. And, inhibition of fatty acid β-oxidation partially blocked FGF21-induced protection in cardiomyocytes. Further, in vitro and in vivo studies indicated that FGF21-induced cardiac protection against type 2 diabetes was mainly attributed to lipotoxicity rather than glucose toxicity. These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK–AKT2–NRF2-mediated antioxidative pathway and AMPK–ACC–CPT-1-mediated lipid-lowering effect in the heart.
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