肝脏糖异生的分子机制研究进展

Recent advances in molecular mechanisms of hepatic gluconeogenesis

肝脏糖异生是肝糖代谢的重要组成部分,受一系列转录因子的调控,其中FoxO1、CREB、PGC-1α与激素和糖异生限速酶葡萄糖-6-磷酸酶(G-6-Pase)和磷酸烯醇式丙酮酸羧化酶(PEPCK)编码基因的串话是决定糖异生启动的关键环节.另外诸多因素,如孤儿核受体Nur77和TR4、细胞因子抵抗素和脂联素、游离脂肪酸直接与转录因子结合,通过多种信号转导通路抑制或增强转录因子的活性,从而影响糖异生限速酶编码基因的转录.肝脏糖异生紊乱导致的肝糖输出增多是机体肝脏胰岛素抵抗发生的重要诱因,因此通过干预肝脏糖异生信号通路的不同环节,减少肝糖生成,将为治疗肝脏胰岛素抵抗综合征及新药研发提供广阔的前景.

As an important part of glucose metabolism in liver, hepatic gluconeogenesis is regulated by a series of transcription factors. FoxO1, CREB and PGC-1α cross talk with insulinor glucagon-responsive transcription genes encoding the rate-limiting enzymes such as glucose-6-phosphatase （G-6-Pase） and phosphoenolpyruvate carboxykinase （PEPCK）, which stimulate hepatic gluconeogenesis. In addition, many regulators such as orphan nuclear receptor Nur77 and TR4, cytokines resistin and adiponectin, free fatty acids, directly bound to transcription factors, repress or enhance their activity, hence affect the transcription. In insulin-resistance diseases, high blood glucose is often induced by the disturbed hepatic gluconeogenesis, and the transcription factors in gluconeogeneic signal pathways are potential therapeutic target.So controlling these transcription factors can decrease hepatic glucose production and effectively treat insulin-resistance syndrome.