维生素B6激活AMPK抗非酒精性脂肪肝病及机制研究

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The pathophysiological process of NAFLD is associated with the increased lipid deposition, oxidative stress, and apoptosis in hepatic cells, all of which are reversed or delayed by activation AMP-activated protein kinase (AMPK). We have previously reported that supplementation of vitamin B6 (VitB6) improved metabolic syndrome and reduced lipid deposition in liver. Our exciting preliminary data further indicated that VitB6 interacted with AMPK-β1 subunit and increased AMPK-α2 phosphorylation in cultured hepatic cells, and protected liver functions in mice injected with LPS. Phenotype of AMPK-α2 gene knockout in mice reveals that the lipid content in liver was increased. Thus, we hypothesized that VitB6 via direct activation of AMPK reduces lipid deposition, oxidative stress, and apoptosis in hepatic cells, resulting in the suppression of NAFLD. Comprehensive experimental approaches, including pharmacological and genetic means, will be used (1) to identity if and how AMPK is activated by VitB6, (2) to investigate whether AMPK activation by VitB6 is critical to the normalizations of hepatic cellular functions and the suppression of NAFLD in vivo, and (3) to establish the clinical link among AMPK, VitB6 and NAFLD. These powerful combinations of in vitro and in vivo techniques and gain/loss-of-function approaches will yield important insights into how VitB6 via AMPK activation prevents from NAFLD and provide the perspective application of VitB6 on treating NAFLD patients.

非酒精性脂肪肝病（NAFLD）是以弥漫性肝细胞大泡性脂肪变为主要病理特征，与肝细胞内脂肪沉积及肝细胞凋亡密切相关。AMPK是细胞能量代谢的感受器和调节器，激活后能促进脂肪代谢，抑制细胞凋亡。我们发现补充维生素B6能改善代谢综合征，抑制肝脏的脂肪沉积。预实验发现维生素B6能与AMPK直接结合并激活AMPK，抑制肝细胞的脂质沉积、炎症反应及凋亡，保护肝功能；敲除AMPK加重了肝脏脂质沉积和脂肪样变。据此，我们设想“维生素B6通过直接激活AMPK而抑制肝细胞内脂肪沉积和肝细胞凋亡，从而具有抗NAFLD作用”。为验证该假说，本课题拟用相应的生物学研究手段，分别在分子、细胞、动物及临床等水平，研究维生素B6如何激活AMPK，确立AMPK在维生素B6抗NAFLD中的作用，明确维生素B6缺乏是NAFLD的新危险因素。本研究将解析维生素B6抗NAFLD的分子机制，为临床防治NAFLD提供新理论和新靶点。

非酒精性脂肪肝病（NAFLD）是以弥漫性肝细胞大泡性脂肪变为主要病理特征，与肝细胞内脂肪沉积及肝细胞凋亡密切相关。AMPK是细胞能量代谢的感受器和调节器，激活后能促进脂肪代谢，抑制细胞凋亡。我们发现补充维生素B6能改善代谢综合征，抑制肝脏的脂肪沉积。预实验发现维生素B6能与AMPK直接结合并激活AMPK，抑制肝细胞的脂质沉积、炎症反应及凋亡，保护肝功能；敲除AMPK加重了肝脏脂质沉积和脂肪样变。据此，我们设想“维生素B6通过直接激活AMPK而抑制肝细胞内脂肪沉积和肝细胞凋亡，从而具有抗NAFLD作用”。我们用先进的生物学研究手段，确定了VitB6激活AMPK的分子机制，VitB6通过AMPK抑制肝细胞脂质沉积、氧化应激、炎症和凋亡，在整体动物证实了AMPK在VitB6抗NAFLD中的作用，在临床水平建立了VitB6、AMPK和NAFLD之间的相关性。本研究解析了维生素B6抗NAFLD的分子机制，为临床防治NAFLD提供新理论和新靶点。