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 ... -  《-》

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 ... -  《-》

Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart.

Yang H ，Feng A ，Lin S ，Yu L ，Lin X ，Yan X ，Lu X ，Zhang C ... -  《Cell Death & Disease》

Fibroblast growth factor 21 deletion aggravates diabetes-induced pathogenic changes in the aorta in type 1 diabetic mice.

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

Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity. The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver.

Ye D ，Wang Y ，Li H ，Jia W ，Man K ，Lo CM ，Wang Y ，Lam KS ，Xu A ... -  《-》