Yu Yinhang, Bai Fuliang, Liu Yaonan, Yang Yongbi, Yuan Qingyan, Zou Dehua, Qu Susu, Tian Guiyou, Song Liying, Zhang Tong, Li Siming, Liu YunYe, Wang Wenfei, Ren Guiping, Li Deshan
Bio-pharmaceutical Lab, Life Science College, Northeast Agricultural University, Harbin, 150030, China,
Mol Cell Biochem. 2015 May;403(1-2):287-99. doi: 10.1007/s11010-015-2358-6. Epub 2015 Feb 21.
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.
成纤维细胞生长因子21（FGF21）是最近发现的对葡萄糖和脂质代谢具有多效性作用的因子。然而，FGF21对D-半乳糖诱导的肝脏损伤的潜在保护作用尚未得到证实。本研究的目的是探讨FGF21在D-半乳糖诱导的小鼠肝脏氧化损伤和细胞凋亡中的病理生理作用。将3月龄昆明小鼠皮下注射D-半乳糖（180 mg kg⁻¹ d⁻¹），持续8周，并同时给予FGF21（5或1 mg kg⁻¹ d⁻¹）。我们的结果表明，给予FGF21可显著减轻D-半乳糖诱导的组织学损伤，包括肝细胞结构破坏、变性和坏死，并以剂量依赖的方式减轻肝损伤标志物、血清天冬氨酸转氨酶（AST）和碱性磷酸酶（ALP）的升高。FGF21治疗还抑制了D-半乳糖诱导的活性氧生成和氧化应激的显著升高，这可通过肝脏中丙二醛（MDA）水平的升高和细胞内谷胱甘肽（GSH）水平的消耗来证明，并恢复了抗氧化酶超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）和总抗氧化能力（T-AOC）的活性。此外，FGF21治疗增加了核因子E2相关因子2（Nrf2）的核丰度，并随后上调了几种抗氧化基因。此外，TUNEL检测表明，FGF21可显著抑制D-半乳糖诱导的小鼠肝脏细胞凋亡。FGF21治疗显著抑制了D-半乳糖处理小鼠肝脏中半胱天冬酶-3（caspase-3）的表达。磷脂酰肌醇-3激酶（PI3K）和蛋白激酶B（PBK）/蛋白激酶B（Akt）的水平也显著升高，这反过来又使促凋亡信号事件失活，恢复了D-半乳糖处理小鼠肝脏中促凋亡和抗凋亡的B细胞淋巴瘤-2（Bcl-2）和Bax蛋白之间的平衡。总之，这些结果表明，FGF21通过增强Nrf2介导的抗氧化能力保护小鼠肝脏免受D-半乳糖诱导的肝细胞氧化应激，并通过激活PI3K/Akt途径保护细胞凋亡。
