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Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice.
Clin Sci (Lond) 2016; 130(8):625-41CS

Abstract

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.

Authors+Show Affiliations

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.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.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.The First Hospital of Jilin University, Changchun 130021, 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. Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.The First Hospital of Jilin University, Changchun 130021, China.Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.The Chinese-American Research Institute for Diabetic Complications, the Wenzhou Medical University, Wenzhou 325035, China lzqlr@medmail.com.cn zhangchi515@126.com l0cai001@louisville.edu.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 lzqlr@medmail.com.cn zhangchi515@126.com l0cai001@louisville.edu.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. lzqlr@medmail.com.cn zhangchi515@126.com l0cai001@louisville.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26795437

Citation

Zhang, Jingjing, et al. "Fenofibrate Increases Cardiac Autophagy Via FGF21/SIRT1 and Prevents Fibrosis and Inflammation in the Hearts of Type 1 Diabetic Mice." Clinical Science (London, England : 1979), vol. 130, no. 8, 2016, pp. 625-41.
Zhang J, Cheng Y, Gu J, et al. Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. Clin Sci. 2016;130(8):625-41.
Zhang, J., Cheng, Y., Gu, J., Wang, S., Zhou, S., Wang, Y., ... Cai, L. (2016). Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. Clinical Science (London, England : 1979), 130(8), pp. 625-41. doi:10.1042/CS20150623.
Zhang J, et al. Fenofibrate Increases Cardiac Autophagy Via FGF21/SIRT1 and Prevents Fibrosis and Inflammation in the Hearts of Type 1 Diabetic Mice. Clin Sci. 2016;130(8):625-41. PubMed PMID: 26795437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice. AU - Zhang,Jingjing, AU - Cheng,Yanli, AU - Gu,Junlian, AU - Wang,Shudong, AU - Zhou,Shanshan, AU - Wang,Yuehui, AU - Tan,Yi, AU - Feng,Wenke, AU - Fu,Yaowen, AU - Mellen,Nicholas, AU - Cheng,Rui, AU - Ma,Jianxing, AU - Zhang,Chi, AU - Li,Zhanquan, AU - Cai,Lu, Y1 - 2016/01/21/ PY - 2015/09/01/received PY - 2016/01/21/accepted PY - 2016/1/23/entrez PY - 2016/1/23/pubmed PY - 2016/7/19/medline KW - FGF21-knockout KW - PPARα agonist (fibrate) KW - Sirt1 KW - autophagy KW - diabetic cardiomyopathy SP - 625 EP - 41 JF - Clinical science (London, England : 1979) JO - Clin. Sci. VL - 130 IS - 8 N2 - 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. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/26795437/Fenofibrate_increases_cardiac_autophagy_via_FGF21/SIRT1_and_prevents_fibrosis_and_inflammation_in_the_hearts_of_Type_1_diabetic_mice_ L2 - http://clinsci.org/cgi/pmidlookup?view=long&pmid=26795437 DB - PRIME DP - Unbound Medicine ER -