乙肝病毒X蛋白结合蛋白通过下调PEPCK的表达抑制肝脏糖异生（英文）

Hepatitis B X-interacting Protein Restrains Hepatic Gluconeogenesis Through Suppressing The Expression of PEPCK

乙肝病毒X蛋白结合蛋白(hepatitis B X-interacting protein,HBXIP)可以调节乳腺癌中糖代谢重编程.为了研究HBXIP在生理条件下对糖代谢的调节作用及机制,本研究利用Cre/lox P重组酶系统成功构建了肝脏组织中HBXIP特异敲除小鼠.当小鼠接受刺激后,与正常组小鼠相比,肝脏HBXIP敲除小鼠表现基础糖代谢功能异常,如葡萄糖、丙酮酸;相对于对照小鼠,肝脏HBXIP敲除小鼠对糖异生和胰岛素耐受性减弱. RT-PCR、Western blot实验和免疫组化实验结果表明,HBXIP敲除小鼠肝脏组织中糖异生关键酶磷酸烯醇式丙酮酸羧化酶(phosphoenolpyruvate carboxykinase,PEPCK)表达显著增加. QRT-PCR分析30例临床肝组织中HBXIP m RNA和PEPCK m RNA表达水平发现,HBXIP与PEPCK表达水平呈负相关.荧光素酶报告基因实验和Ch IP实验结果表明HBXIP可以在基因转录水平调节PEPCK表达.以上结果表明,HBXIP通过调节糖异生关键酶PEPCK的表达参与调控小鼠肝脏糖异生.

Hepatitis B X-interacting protein(HBXIP) is able to mediate glucose metabolism reprogramming in breast cancer. To investigate the physiological functions of HBXIP in regulation of glucose metabolism, we generated liver-specific HBXIP conditional knockout C57 BL/6 mice using Cre/lox P approach. Liver HBXIP-/-mice exhibited a phenotype of glycometabolic dysregulation, such as higher fasting blood glucose level, accumulation of hepatic glycogen, recession of blood glucose profiles, and elevation of gluconeogenesis. The expression levels of PEPCK were remarkably up-regulated in the liver tissues of HBXIP-/-mice.Then, we validated that HBXIP expressions were negatively correlated with those of PEPCK in 30 clinical liver tissues.Mechanistically, luciferase reporter gene assays and Ch IP assays showed that HBXIP could inhibit the expression PEPCK at transcription level. Taken together, our findings indicate that HBXIP restrains hepatic gluconeogenesis through suppressing the expression of PEPCK.