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.
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Radiation nephropathy is mitigated by EET-A and also by captopril. The severe histological injury of radiation nephropathy includes cast formation and mesangiolysis. Both are significantly attenuated by EET-A or captopril. PAS stained kidney, 200x magnification. For further details see pp. 587–599. Image kindly provided by Dr. Md Abdul Hye Khan.
Research Article|
March 08 2016
Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice
Jingjing Zhang;
Jingjing Zhang
*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.
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Yanli Cheng;
Yanli Cheng
‡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
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Junlian Gu;
Junlian Gu
‡Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.
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Shudong Wang;
Shudong Wang
‡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
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Shanshan Zhou;
Shanshan Zhou
‡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
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Yuehui Wang;
Yuehui Wang
§The First Hospital of Jilin University, Changchun 130021, China
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Yi Tan;
Yi Tan
†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.
║Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.
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Wenke Feng;
Wenke Feng
║Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.
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Yaowen Fu;
Yaowen Fu
§The First Hospital of Jilin University, Changchun 130021, China
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Nicholas Mellen;
Nicholas Mellen
‡Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.
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Rui Cheng;
Rui Cheng
¶Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.
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Jianxing Ma;
Jianxing Ma
¶Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.
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Chi Zhang;
†The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China
Correspondence: Dr Zhanquan Li (email [email protected]), Dr Chi Zhang (email [email protected]) or Dr Lu Cai (email [email protected])
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Zhanquan Li;
*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
Correspondence: Dr Zhanquan Li (email [email protected]), Dr Chi Zhang (email [email protected]) or Dr Lu Cai (email [email protected])
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Lu Cai
†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.
║Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.
Correspondence: Dr Zhanquan Li (email [email protected]), Dr Chi Zhang (email [email protected]) or Dr Lu Cai (email [email protected])
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Publisher: Portland Press Ltd
Received:
September 01 2015
Revision Received:
January 04 2016
Accepted:
January 21 2016
Accepted Manuscript online:
January 21 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (8): 625–641.
Article history
Received:
September 01 2015
Revision Received:
January 04 2016
Accepted:
January 21 2016
Accepted Manuscript online:
January 21 2016
Citation
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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