The role of vasodilator-stimulated phosphoprotein (VASP) in the control of hepatic gluconeogenic gene expression

During periods in which glucose absorption from the gastrointestinal (GI) tract is insufficient to meet body requirements, hepatic gluconeogenesis plays a key role to maintain normal blood glucose levels. The current studies investigated the role in this process played by vasodilatory-associated phosphoprotein (VASP), a protein that is phosphorylated in hepatocytes by cAMP/protein kinase A (PKA), a key mediator of the action of glucagon. We report that following stimulation of hepatocytes with 8Br-cAMP, phosphorylation of VASP preceded induction of genes encoding key gluconeogenic enzymes, glucose-6-phosphatase (G6p) and phosphoenolpyruvate carboxykinase (Pck1), and that VASP overexpression enhanced this gene induction. Conversely, hepatocytes from mice lacking VASP (Vasp-/-) displayed blunted induction of gluconeogenic enzymes in response to cAMP, and Vasp-/- mice exhibited both greater fasting hypoglycemia and blunted hepatic gluconeogenic enzyme gene expression in response to fasting in vivo. These effects of VASP deficiency were associated with reduced phosphorylation of both CREB (a key transcription factor for gluconeogenesis that lies downstream of PKA) and histone deacetylase 4 (HDAC4), a combination of effects that inhibit transcription of gluconeogenic genes. These data support a model in which VASP functions as a molecular bridge linking the two key signal transduction pathways governing hepatic gluconeogenic gene expression.

当胃肠道 (gastrointestinal tract, GI) 对葡萄糖的吸收不足以满足机体需求时，肝脏糖异生 (hepatic gluconeogenesis) 在维持正常血糖水平中发挥关键作用。本研究探讨了血管舒张相关磷蛋白 (vasodilatory-associated phosphoprotein, VASP) 在该过程中的调控作用：该蛋白可在肝细胞 (hepatocytes) 中被环腺苷酸/蛋白激酶A (cAMP/protein kinase A, PKA) 磷酸化，而PKA是胰高血糖素 (glucagon) 发挥生理作用的关键介导因子。研究结果显示：采用8-溴代环腺苷酸 (8Br-cAMP) 刺激肝细胞后，VASP的磷酸化先于两类关键糖异生酶编码基因——葡萄糖-6-磷酸酶 (glucose-6-phosphatase, G6p) 与磷酸烯醇式丙酮酸羧激酶 (phosphoenolpyruvate carboxykinase, Pck1)——的诱导表达；且VASP过表达可显著增强该基因诱导效应。反之，Vasp基因敲除（Vasp-/-）小鼠的肝细胞在接受cAMP刺激时，其糖异生酶的诱导表达出现明显受抑；而在体禁食实验中，Vasp-/-小鼠不仅表现出更严重的禁食性低血糖，其肝脏糖异生酶的基因表达也出现显著减弱。VASP缺失引发的上述效应，与环腺苷酸应答元件结合蛋白 (CREB，PKA下游的糖异生关键转录因子) 及组蛋白去乙酰化酶4 (histone deacetylase 4, HDAC4) 的磷酸化水平降低密切相关；二者磷酸化水平的下降会协同抑制糖异生基因的转录。本研究数据支持如下模型：VASP作为分子桥梁，连接了调控肝脏糖异生基因表达的两条关键信号转导通路 (signal transduction pathways)。