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

摘要: 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 prevent pathogenesi of heart in Type 1 diabetes and describe underlying mechanism its action. Streptozotocin (STZ)-induced diabetic mice their age-matched control were treated with vehicle or by gavage every other day 3 6 months. prevented diabetes-induced cardiac dysfunction (e.g. decreased ejection fraction hypertrophy), inflammation remodelling. also increased expression fibroblast growth factor 21 (FGF21) sirtuin (Sirt1) non-diabetic conditions. Deletion FGF21 gene (FGF21-KO) worsened pathogenic effects heart. treatment deterioration wild-type mice, but could not do so FGF21-KO although systemic profile was lowered both mice. Mechanistically, diabetes-impaired autophagy, reflected microtubule-associated protein 1A/1B-light chain 3, Studies H9C2 cells vitro demonstrated that exposure high glucose (HG) significantly inflammatory response, oxidative stress pro-fibrotic response inhibited autophagy. These HG treatment. Inhibition either autophagy 3-methyladenine (3MA) Sirt1 sirtinol (SI) abolished FF's prevention HG-induced effects. results suggested pathological functional abnormalities increasing may up-regulate Sirt1-mediated