游离脂肪酸和铁在非酒精性脂肪肝发病过程中的联合作用及其机制研究

Large amounts of free fatty acids (FFAs) are oxidized in the mitochondria of hepatocytes, leading to oxidative stress and lipid peroxidation in the case of non-alcoholic fatty liver disease (NAFLD). Iron can also catalyze the excess production of reactive oxygen species and then result in mitochondrial dysfunction. However, it is unknown whether there exist synergistic effects between FFAs and iron in NAFLD. In the present study, NAFLD models will be established by high fat and high iron diet in rats and by FFAs and iron in hepatocytes. Fatty acid oxidation, frataxin-regulated iron metabolism, oxidative stress, oxidative injury and mitochondrial function will be observed in order to investigated the synergism of FFAs and iron and the roles of frataxin, a mitochondrial protein, in NAFLD. Frataxin siRNA were injected into high fat and high iron diet-induced NAFLD rats. Frataxin overexpressing vectors of siRNA were transfected into hepatocytes. Finally, the association of lipid metabolism and iron with the pathogenesis of NAFLD will be explored in NAFLD patients and controls, aimed at providing the basis for the prevention and therapy of NAFLD and for individual and rational iron supplementation.

非酒精性脂肪肝（NAFLD）时肝细胞内大量的游离脂肪酸（FFAs）在线粒体内氧化，引起氧化应激和脂质过氧化；铁也可催化产生过量的活性氧，引起线粒体功能障碍，而FFAs和铁在NAFLD发病过程中是否存在联合作用亟待探讨。本研究拟采用高脂和高铁膳食诱导NAFLD动物模型，采用FFAs和铁诱导NAFLD肝细胞模型，观察对线粒体内脂肪酸氧化、frataxin调节的铁代谢、氧化应激、氧化损伤和线粒体功能的影响，阐明FFAs和铁在NAFLD病情发展过程中的联合作用及线粒体蛋白frataxin的作用。动物注射frataxin siRNA，体外转染过表达载体或siRNA，从正反两方面明确frataxin是否为FFAs和铁引起线粒体损伤中共同作用的靶点。最后探讨人群中脂类代谢、铁与NAFLD发病的相关性，将为NAFLD的预防和治疗奠定理论基础，同时也为不同人群科学合理地补铁提供科学依据。

非酒精性脂肪肝（NAFLD）时肝细胞内大量的游离脂肪酸（FFAs）在线粒体内氧化，引起氧化应激和脂质过氧化；铁也可催化产生过量的活性氧，引起线粒体功能障碍，而FFAs和铁在NAFLD发病过程中是否存在联合作用亟待探讨。本研究采用高脂和高铁饮食诱导NAFLD动物模型，采用FFAs和铁诱导NAFLD肝细胞模型，观察对脂肪酸氧化、氧化应激、氧化损伤和线粒体功能的影响，并探讨人群中FFAs和铁与NAFLD发病的相关性。动物和细胞实验结果显示，高脂和高铁引起典型的NAFLD病理改变和肝脏损伤，联合时脂质堆积和损伤程度重于高脂单独的作用。主要通过改变脂肪酸合成和β-氧化以及铁代谢关键基因的表达，引起线粒体功能障碍和氧化应激，降低抗氧化活性，从而引起脂质代谢和铁代谢异常。去铁胺可改善脂质堆积和肝脏损伤的程度。人群试验结果显示，炎症因子IL-6和TNF-a水平在NAFLD人群中明显升高，提示二者在非酒精性脂肪肝病的发生发展中可能发挥重要作用。通过问卷调查，发现NAFLD人群生活方式不健康，NAFLD知识-态度-行为认知度不高，膳食结构不合理，营养素摄入不均衡，高膳食铁及血红素铁摄入是NAFLD患病的危险因素。本研究阐明了FFAs和铁在NAFLD病情发展过程中的联合作用，为NAFLD的预防和治疗奠定了理论和实践基础，同时也为不同人群科学合理地补铁提供科学依据，并建议对NAFLD人群进行健康教育与合理的生活及饮食干预。