Fibroblast growth factor (FGF21) protects mouse liver against d-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways

Abstract

FGF21 is recently discovered with pleiotropic effects on glucose and lipid metabolism. However, the potential protective effect of FGF21 against D-gal-induced injury in the liver has not been demonstrated. The aim of this study is to investigate the pathophysiological role of FGF21 on hepatic oxidative injury and apoptosis in mice induced by D-gal. The 3-month-old Kunming mice were subcutaneously injected with D-gal (180 mg kg(-1) d(-1)) for 8 weeks and administered simultaneously with FGF21 (5 or 1 mg kg(-1) d(-1)). Our results showed that the administration of FGF21 significantly alleviated histological lesion including structure damage, degeneration, and necrosis of hepatocytes induced by D-gal, and attenuated the elevation of liver injury markers, serum AST, and ALP in a dose-dependent manner. FGF21 treatment also suppressed D-gal-induced profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level in the liver, and restored the activities of antioxidant enzymes SOD, CAT, GSH-Px, and T-AOC. Moreover, FGF21 treatment increased the nuclear abundance of Nrf2 and subsequent up regulation of several antioxidant genes. Furthermore, a TUNEL assay showed that D-gal-induced apoptosis in the mouse liver was significantly inhibited by FGF21. The expression of caspase-3 was markedly inhibited by the treatment of FGF21 in the liver of D-gal-treated mice. The levels of PI3K and PBK/Akt were also largely enhanced, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 and Bax proteins in the liver of D-gal-treated mice. In conclusion, these results suggest that FGF21 protects the mouse liver against D-gal-induced hepatocyte oxidative stress via enhancing Nrf2-mediated antioxidant capacity and apoptosis via activating PI3K/Akt pathway.

Effects of fibroblast growth factor 21 on the heart

“…Sirt1, sirtuin 1; UCP3, uncoupling protein-3; Sod2, superoxide dismutase-2; Prdx2/5, peroxiredoxin-2/5; Cat, catalase; GPX1, glutathione peroxidase 1; Sqstm1, sequestosome 1; ROS, reactive oxygen species; Nrf2, Nuclear factor erythroid 2-related factor 2; PI3K, phosphatidylinositol 3-kinase. Data from Planavila et al (2014) and Yu et al (2015). improved cardiac function in cardiac I/R injury (Cong et al 2013, Liu et al 2013, Patel et al 2014, cardiac hypertrophy (Planavila et al 2013), and DCM (Zhang et al 2015a) supported this hypothesis.…”

“…This leads to the phosphorylation of FRS2a, and subsequent activation of PI3K (Liu et al 2013, Patel et al 2014, Yu et al 2015 following its phosphorylation at Serin458 [G dp/dt, %FS FGF21 decreases cellular apoptosis and increases cardiac function due to I/R injury through an activation of FGFR1/b-Klotho-PI3K-Akt1-BAD signaling. Liu et al (2013) [ FGF21 sensitivity .…”

“…n the autocrine loop function, FGF21 induces anti-oxidant gene expression through the Erk/Sirt1 pathway, including uncoupling protein 3 (UCP3), superoxide dismutase 2 (Sod 2), peroxiredoxin 5 (Prdx5), glutathione peroxidase 1 (GPX1), Catalase (CAT) and Sequestosome 1 (Sqstm1), resulting in a reduction in cardiac tissue injury (Planavila et al 2014). Furthermore, FGF21 has been shown to activate the Nrf2 pathway in hepatocytes, which was found to lead to increased anti-oxidant gene expression, resulting in the reduction of liver tissue injury (Yu et al 2015) (Fig. 6).…”

“…This indicated that FGF21 could protect the cardiomyocytes or slow down the degree of damage following oxidative stress in a failing human heart. It has been shown that these signaling pathways of FGF21 have the crosstalk at the secondary messenger levels such as ERK1/2 for anti-apoptosis (Zhang et al 2015a), anti-hypertrophic (Planavila et al 2013(Planavila et al , 2014, and anti-oxidative stress (Yu et al 2015) in the heart. Activation of FGFR/b-Klotho complex therefore could activate these effects of FGF21 simultaneously at this crosstalk.…”

“…Under stress conditions, FGF21 has been shown to reduce the apoptosis of Islet b cells (Wente et al 2006), hepatocytes (Yu et al 2015), vascular cells (Wu et al 2014), cardiac endothelial cells (Lu et al 2010) and cardiomyocytes (Cong et al 2013, Liu et al 2013. Interestingly, FGF21 also protects the heart from apoptosis and remodeling through the activation of adiponectin release to activate the adiponectin signaling pathways (Joki et al 2015).…”