Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice
Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice
复制标题
非诺贝特通过 FGF21/SIRT1 增加心脏自噬，并预防 1 型糖尿病小鼠心脏的纤维化和炎症
DOI：
10.1042/cs20150623
复制
发表时间：
2016
期刊：
影响因子：
6
通讯作者：
Cai Lu
中科院分区：
文献类型：
--
作者：
Zhang Jingjing;Cheng Yanli;Gu Junlian;Wang Shudong;Zhou Shanshan;Wang Yuehui;Tan Yi;Feng Wenke;Fu Yaowen;Mellen Nicholas;Cheng Rui;Ma Jianxing;Zhang Chi;Li Zhanquan;Cai Lu
非诺贝特作为一种过氧化物酶体增殖物激活受体α(PPARα)激动剂，几十年来一直用于临床降脂。在本研究中，我们研究了FF是否可以被重新利用来预防1型糖尿病患者的心脏发病机制，并描述其作用的潜在机制。链脲佐菌素(STZ)诱导的糖尿病小鼠及其年龄匹配的对照组小鼠每隔一天给予赋形剂或FF灌胃，连续3个月或6个月。FF可预防糖尿病引起的心脏功能障碍(如射血分数降低和肥厚)、炎症和重塑。在非糖尿病和糖尿病情况下，FF还增加了心脏成纤维细胞生长因子21(FGF21)和sirtuin 1(Sirt1)的表达。FGF21基因缺失(FGF21-KO)加重了糖尿病引起的心脏致病效应。FF治疗可防止野生型糖尿病小鼠的心脏恶化，但对FGF21-KO糖尿病小鼠却不起作用，尽管野生型和FGF21-KO糖尿病小鼠的全身血脂水平都有所降低。从机制上讲，在野生型糖尿病小鼠中，FF治疗可以防止糖尿病受损的自噬，表现为微管相关蛋白1A/1B轻链3的增加，但在FGF21-KO糖尿病小鼠中则不能。体外对H9C2细胞的研究表明，暴露在高糖(HG)中显著增加了炎症反应、氧化应激和促纤维化反应，并显著抑制了自噬。HG的这些效应可被福尔马林治疗所阻止。用3-甲基腺嘌呤(3MA)或sirtinol(SI)抑制Sirt1自噬均可阻断FF对HG诱导的效应的预防作用。这些结果表明，FF可以通过增加FGF21来预防1型糖尿病引起的心脏病理和功能异常，FGF21可能上调Sirt1介导的自噬。
Fenofibrate (FF), as a peroxisome-proliferator-activated receptor α (PPARα) agonist, has been used clinically for decades to lower lipid levels. In the present study, we examined whether FF can be repurposed to prevent the pathogenesi of the heart in Type 1 diabetes and to describe the underlying mechanism of its action. Streptozotocin (STZ)-induced diabetic mice and their age-matched control mice were treated with vehicle or FF by gavage every other day for 3 or 6 months. FF prevented diabetes-induced cardiac dysfunction (e.g. decreased ejection fraction and hypertrophy), inflammation and remodelling. FF also increased cardiac expression of fibroblast growth factor 21 (FGF21) and sirtuin 1 (Sirt1) in non-diabetic and diabetic conditions. Deletion of FGF21 gene (FGF21-KO) worsened diabetes-induced pathogenic effects in the heart. FF treatment prevented heart deterioration in the wild-type diabetic mice, but could not do so in the FGF21-KO diabetic mice although the systemic lipid profile was lowered in both wild-type and FGF21-KO diabetic mice. Mechanistically, FF treatment prevented diabetes-impaired autophagy, reflected by increased microtubule-associated protein 1A/1B-light chain 3, in the wild-type diabetic mice but not in the FGF21-KO diabetic mice. Studies with H9C2 cellsin vitrodemonstrated that exposure to high glucose (HG) significantly increased inflammatory response, oxidative stress and pro-fibrotic response and also significantly inhibited autophagy. These effects of HG were prevented by FF treatment. Inhibition of either autophagy by 3-methyladenine (3MA) or Sirt1 by sirtinol (SI) abolished FF's prevention of HG-induced effects. These results suggested that FF could prevent Type 1 diabetes-induced pathological and functional abnormalities of the heart by increasing FGF21 that may up-regulate Sirt1-mediated autophagy.