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.
Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice
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Jingjing Zhang, Yanli Cheng, Junlian Gu, Shudong Wang, Shanshan Zhou, Yuehui Wang, Yi Tan, Wenke Feng, Yaowen Fu, Nicholas Mellen, Rui Cheng, Jianxing Ma, Chi Zhang, Zhanquan Li, Lu Cai; Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. Clin Sci (Lond) 1 April 2016; 130 (8): 625–641. doi: https://doi.org/10.1042/CS20150623
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