Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of type 1 diabetic mice

Fenofibrate (FF), as a peroxisome proliferator-activated receptor-α agonist, has been used clinically for decades tolower lipid levels. Here we examined whether FF can be repurposed to prevent the pathogenies of the heart in type 1 diabetes and to describe the underlying mechanism of its action. Streptozotocin-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 remodeling. 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 though 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 F...

Source: Clinical Science - January 21, 2016 Category: Biomedical Science Authors: Zhang, J., Cheng, Y., Gu, J., Wang, S., Zhou, S., Wang, Y., Tan, Y., Feng, W., Fu, Y., Mellen, N., Cheng, R., Ma, J., Zhang, C., Li, Z., Cai, L. Tags: PublishAheadOfPrint Source Type: research