Abstract
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.
Highlights
In the fasting state, increased hepatic gluconeogenesis is essential to avert hypoglycemia and maintain normal plasma glucose levels
The combination of reduced plasma insulin and increased plasma glucagon levels supports the maintenance of normal blood glucose levels by inducing hepatic gluconeogenesis via a mechanism involving both reduced hepatocyte forkhead box o1 (FOXO1) and increased cAMP/protein kinase A (PKA) signaling, leading to Pck1 and G6p gene expression [1, 2]
Since PKA phosphorylates vasodilatory-associated phosphoprotein (VASP) on serine157 in other cell types [18, 19], we first tested whether cAMP stimulation increases VASP ser157 phosphorylation in hepatocytes, and if so, whether this occurs over a time course consistent with a role in gluconeogenesis
Summary
In the fasting state, increased hepatic gluconeogenesis is essential to avert hypoglycemia and maintain normal plasma glucose levels. Glucagon and epinephrine are key hormonal drivers of gluconeogenesis by virtue of increased intracellular cAMP levels induced by binding of their respective receptors on the hepatocyte plasma membrane. Locke Jr. Charitable Trust and from the Kenneth H. Cooper Endowed Professorship in Preventive Cardiology (to FK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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