title: Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice.
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.affiliation: 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.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.
authors.forename: Junlian
authors.initials: J
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Departments of Medicine and Pharmacology & Toxicology, University of Louisville, Louisville 40202, KY, U.S.A.
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.affiliation: The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, KY, U.S.A.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mellen
authors.affiliation: Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Physiology, the University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, U.S.A.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhanquan
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011345:Fenofibrate / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D056572:Histone Deacetylase Inhibitors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D011345:Fenofibrate
keywords: FGF21-knockout; PPARα agonist (fibrate); Sirt1; autophagy; diabetic cardiomyopathy