GLRX调控的PGC-1alpha脂肪酸beta氧化通路与非酒精性脂肪肝病的致病机制研究

Non-alcoholic fatty liver disease is a common liver disease associated with aging that is rising in prevalence worldwide. The molecular mechanisms leading to non-alcoholic fatty liver disease are incompletely understood. Recent studies have indicated that a hyperlipidemic environment in the liver increases oxidative stress. Glutaredoxin-1 (GLRX) is a specific and efficient thioltransferase that removes protein S-glutathionylation which mediate redox signaling. GLRX is abundant in the liver but its role in liver pathophysiology is unknown. Here we report that chow-fed GLRX KO mice show aging related hepatic steatosis, worse after fasting for 24 hours, suggesting an essential role of hepatic GLRX in the pathogenesis of steatosis through regulating fatty acid beta oxidation pathway. PGC-1alpha, an important regulator of fatty acid beta oxidation, with aging related increased reversible oxidation in GLRX KO mice, suggesting that PGC-1alpha is a target mediating the effects of GLRX on pathogenesis of steatosis. Therefore, I hypothesize that depleting GLRX induces lipid metabolic disorder by increasing PGC-1alpha S-glutathionylation in liver, impairing its activity in PPARalpha mediated fatty acid beta oxidation pathway and this leads to aging related hepatic steatosis.

非酒精性脂肪肝病（NAFLD）是目前临床上中老年人最常见的慢性肝病。最近研究表明，肝脏中脂代谢异常与衰老引起的氧化还原态失衡相关。谷氧还原蛋-1（GLRX）能特异性去除介导氧化还原信号通路的蛋白S-谷胱甘肽修饰，但在肝脏中调节脂代谢途径的作用尚不清楚。我们前期研究发现，正常饮食的GLRX敲除（KO）小鼠随年龄增长表现出脂肪肝的特征，在饥饿情况下表现更为显著，提示肝脏GLRX在调节脂肪酸beta氧化过程中的重要作用；PGC-1alpha为重要的脂肪酸beta氧化调节因子，在GLRX KO小鼠肝脏中随年龄增长氧化还原修饰增加。本研究探讨随年龄增长GLRX在肝脏中通过调节PGC-1alpha的S-谷胱甘肽化修饰，进一步调控协同刺激核受体转录因子PPAR alpha的下游靶基因影响脂肪酸的beta氧化来调控NAFLD的发生, 为衰老相关的NAFLD发生分子机制研究和寻找治疗靶点提供理论依据。

在体外实验中发现，敲低GLRX1，细胞ROS水平和谷胱甘肽化蛋白水平明显升高，诱导细胞衰老凋亡。这可能导致细胞一些重要蛋白发生谷胱甘肽化修饰，从而失去生物学活性，影响细胞表型。通过调控GLRX1的表达，细胞的生长受到抑制，凋亡水平明显升高，这种影响主要是通过促进促凋亡蛋白Bim的表达介导的。敲低GLRX1能通过抑制NF-κB信号通路P65的磷酸化减少COX2的表达和PGE2的生成，进而抑制ERK的磷酸化，促进Bim的表达。其中，pP65的降低可能和敲低GLRX1后p65的谷胱甘肽化水平增加有关。因此，在体外进行细胞凋亡的机制研究，证实GLRX1通过调节p65的谷胱甘肽化水平，在调控细胞增殖中发挥重要作用。

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