eThe phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110␣ is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110␣. Very little is known about the metabolic consequences of the hot spot mutations of p110␣ in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110␣ expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110␣ mutants was surprisingly not dependent on altered p110␣ lipid kinase activity. Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of several signaling pathways, including insulin-like growth factor 1 (IGF-1) and insulin signaling (1). Upon activation by IGF-1, insulin, or other growth factors, it catalyzes the formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), which has a high affinity for the pleckstrin homology (PH) domain of the downstream target Akt/protein kinase B (Akt/ PKB). The interaction of PIP 3 with the PH domain enables phosphorylation of Akt/PKB by phosphoinositide-dependent kinase 1 (PDK 1) and PDK 2. PI3K and Akt/PKB are both critical nodes in many intracellular signaling pathways and are imperative for the actions of IGF-1, insulin, and other growth factors (2).Class IA PI3Ks consist of two subunits. The catalytic subunit, p110, contains the kinase domain responsible for the formation of PIP 3 . The regulatory subunit, usually designated p85, binds to phosphorylated tyrosine residues in other proteins via its SH2 domain, leading to subsequent activation of the kinase. Both subunits exist as several different isoforms. There are four known human catalytic subunit isoforms: p110␣, p110, p110␦, and p37␦. p110␣, p110, and p110␦ are encoded by three different genes, i.e., PIK3CA, PIK3CB, and PIK3CD, respectively (reviewed in reference 1), whereas p37␦ (PIK3CD_v2) is a splice variant of p110␦ (3). We and others have shown that among the catalytic subunits, p110␣ is the major contributor to transmission of the insulin signal (4-6), whereas p110 becomes active primarily in response to G-protein-coupled receptor signaling and plays a role in proliferation (7,8). p110␦ is more cell specific than p110␣ and p110 and plays an important role in immune cells and the embryonic nervous system (9-11).p110␣ is the most frequently mutated kinase in human cancer; three mutations in particular, often referred to as the hot spot mutations, namely, E542K, E545K, and H1047R, are the most common in p110␣ (PIK3CA) and comprise 80% of all mutations (reviewed in ref...
Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.
Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.
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