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 (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.

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 ... -  《-》

Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy.

The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Akt, and GSK-3β phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. All these adverse effects were significantly attenuated by FF treatment. FF also significantly increased fibroblast growth factor 21 (FGF21) expression and enhanced Nrf2 function in diabetic and non-diabetic kidneys. Moreover, FF-induced amelioration of diabetic renal damage, including the stimulation of PI3K/Akt/GSK-3β/Fyn pathway and the enhancement of Nrf2 function were abolished in FGF21-null mice, confirming the critical role of FGF21 in FF-induced renal protection. These results suggest for the first time that FF prevents the development of DN via up-regulating FGF21 and stimulating PI3K/Akt/GSK-3β/Fyn-mediated activation of the Nrf2 pathway.

Cheng Y ，Zhang J ，Guo W ，Li F ，Sun W ，Chen J ，Zhang C ，Lu X ，Tan Y ，Feng W ，Fu Y ，Liu GC ，Xu Z ，Cai L ... -  《-》

FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.

Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1α in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.

Yan X ，Chen J ，Zhang C ，Zhou S ，Zhang Z ，Chen J ，Feng W ，Li X ，Tan Y ... -  《-》

Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.

Chen Y ，Du J ，Zhao YT ，Zhang L ，Lv G ，Zhuang S ，Qin G ，Zhao TC ... -  《Cardiovascular Diabetology》

Insulin replacement limits progression of diabetic cardiomyopathy in the low-dose streptozotocin-induced diabetic rat.

Tate M ，Deo M ，Cao AH ，Hood SG ，Huynh K ，Kiriazis H ，Du XJ ，Julius TL ，Figtree GA ，Dusting GJ ，Kaye DM ，Ritchie RH ... -  《-》