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
Department of Cardiology at the First Hospital of China Medical University, and Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang 110016, China The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.
Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A. The First Hospital of Jilin University, Changchun 130021, China.
Clin Sci (Lond). 2016 Apr;130(8):625-41. doi: 10.1042/CS20150623. Epub 2016 Jan 21.
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 cells in vitro demonstrated 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.
非诺贝特（FF）作为一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，已在临床上用于降低血脂水平数十年。在本研究中，我们研究了FF是否可重新用于预防1型糖尿病心脏的发病机制，并描述其作用的潜在机制。用链脲佐菌素（STZ）诱导糖尿病小鼠，并将其与年龄匹配的对照小鼠每隔一天通过灌胃给予赋形剂或FF，持续3或6个月。FF可预防糖尿病引起的心脏功能障碍（如射血分数降低和心肌肥大）、炎症和重塑。在非糖尿病和糖尿病状态下，FF还可增加心脏中成纤维细胞生长因子21（FGF21）和沉默调节蛋白1（Sirt1）的表达。FGF21基因缺失（FGF21-KO）会加重糖尿病引起的心脏致病作用。FF治疗可预防野生型糖尿病小鼠的心脏恶化，但在FGF21-KO糖尿病小鼠中则无效，尽管野生型和FGF21-KO糖尿病小鼠的全身血脂水平均有所降低。从机制上讲，FF治疗可预防野生型糖尿病小鼠中糖尿病损害的自噬，这表现为微管相关蛋白1A/1B轻链3增加，而在FGF21-KO糖尿病小鼠中则无此作用。体外对H9C2细胞的研究表明，暴露于高糖（HG）会显著增加炎症反应、氧化应激和促纤维化反应，还会显著抑制自噬。FF治疗可预防HG的这些作用。用3-甲基腺嘌呤（3MA）抑制自噬或用sirtinol（SI）抑制Sirt1可消除FF对HG诱导作用的预防。这些结果表明，FF可通过增加FGF21来预防1型糖尿病引起的心脏病理和功能异常，而FGF21可能会上调Sirt1介导的自噬。
