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1.
PLoS One ; 14(4): e0215601, 2019.
Article in English | MEDLINE | ID: mdl-31017943

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.


Subject(s)
Cell Adhesion Molecules/metabolism , Gluconeogenesis/genetics , Liver/metabolism , Microfilament Proteins/metabolism , Phosphoproteins/metabolism , Animals , Blood Glucose/metabolism , Cell Adhesion Molecules/deficiency , Cell Adhesion Molecules/genetics , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Fasting/metabolism , Gene Expression Regulation , Glucose-6-Phosphatase/genetics , Hepatocytes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microfilament Proteins/deficiency , Microfilament Proteins/genetics , Models, Biological , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Phosphoproteins/deficiency , Phosphoproteins/genetics , Phosphorylation , Signal Transduction
2.
Diabetes ; 62(6): 1913-22, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23349495

ABSTRACT

Activation of AMP-activated protein kinase (AMPK) signaling reduces hepatic steatosis and hepatic insulin resistance; however, its regulatory mechanisms are not fully understood. In this study, we sought to determine whether vasodilator-stimulated phosphoprotein (VASP) signaling improves lipid metabolism in the liver and, if so, whether VASP's effects are mediated by AMPK. We show that disruption of VASP results in significant hepatic steatosis as a result of significant impairment of fatty acid oxidation, VLDL-triglyceride (TG) secretion, and AMPK signaling. Overexpression of VASP in hepatocytes increased AMPK phosphorylation and fatty acid oxidation and reduced hepatocyte TG accumulation; however, these responses were suppressed in the presence of an AMPK inhibitor. Restoration of AMPK phosphorylation by administration of 5-aminoimidazole-4-carboxamide riboside in Vasp(-/-) mice reduced hepatic steatosis and normalized fatty acid oxidation and VLDL-TG secretion. Activation of VASP by the phosphodiesterase-5 inhibitor, sildenafil, in db/db mice reduced hepatic steatosis and increased phosphorylated (p-)AMPK and p-acetyl CoA carboxylase. In Vasp(-/-) mice, however, sildendafil treatment did not increase p-AMPK or reduce hepatic TG content. These studies identify a role of VASP to enhance hepatic fatty acid oxidation by activating AMPK and to promote VLDL-TG secretion from the liver.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Cell Adhesion Molecules/metabolism , Fatty Acids/metabolism , Liver/enzymology , Liver/metabolism , Microfilament Proteins/metabolism , Phosphoproteins/metabolism , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Blotting, Western , Cell Adhesion Molecules/genetics , Mice , Mice, Mutant Strains , Microfilament Proteins/genetics , Oxidation-Reduction , Phosphoproteins/genetics , Phosphorylation/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Ribonucleosides/pharmacology
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