Open AccessThe role of vasodilator-stimulated phosphoprotein (VASP) in the control of hepatic gluconeogenic gene expression
Author(s) -
Sanshiro Tateya,
Norma Rizzo-De Leon,
Andrew Cheng,
Brian Dick,
Woo Je Lee,
Madeleine L. Kim,
Kevin D. O’Brien,
Gregory J. Morton,
Michael W. Schwartz,
Francis Kim
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0215601
Subject(s) - phosphoprotein , gluconeogenesis , biology , tyrosine aminotransferase , phosphoenolpyruvate carboxykinase , phosphorylation , signal transduction , endocrinology , microbiology and biotechnology , biochemistry , enzyme inducer , enzyme , metabolism
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.