Dual Effect of the Adapter Growth Factor Receptor-Bound Protein 14 (Grb14) on Insulin Action in Primary Hepatocytes
| Autor: | Anne-Françoise Burnol, Michèle Caüzac, Jean Girard, Nadège Carré |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Biology Mice Endocrinology Internal medicine Insulin receptor substrate medicine Animals Insulin RNA Small Interfering Protein kinase B Adaptor Proteins Signal Transducing Insulin-like growth factor 1 receptor Reverse Transcriptase Polymerase Chain Reaction Akt/PKB signaling pathway GRB10 Proteins Lipids IRS2 Liver Glycogen Mice Inbred C57BL Kinetics Insulin receptor Glucose Hepatocytes biology.protein Sterol Regulatory Element Binding Protein 1 Gene Deletion |
| Zdroj: | Endocrinology. 149:3109-3117 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2007-1196 |
| Popis: | Tight control of insulin action in liver is a crucial determinant for the regulation of energy homeostasis. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter, highly expressed in liver, which binds to the activated insulin receptor and inhibits its tyrosine kinase activity. The physiological role of Grb14 in liver metabolism was unexplored. In this study we used RNA interference to investigate the consequences of Grb14 decrease on insulin-regulated intracellular signaling, and on glucose and lipid metabolism in mouse primary cultured hepatocytes. In Grb14-depleted hepatocytes, insulin-induced phosphorylation of Akt, and of its substrates glycogen synthase kinase 3 and fork-head box protein 1, was increased. These effects on insulin signaling are in agreement with the selective inhibitory effect of Grb14 on the receptor kinase. However, the metabolic and genic effects of insulin were differentially regulated after Grb14 down-regulation. Indeed, the insulin-mediated inhibition of hepatic glucose production and gluconeogenic gene expression was slightly increased. Surprisingly, despite the improved Akt pathway, the induction by insulin of sterol regulatory element binding protein-1c maturation was totally blunted. As a result, in the absence of Grb14, glycogen synthesis as well as glycolytic and lipogenic gene expression were not responsive to the stimulatory effect of insulin. This study provides evidence that Grb14 exerts a dual role on the regulation by insulin of hepatic metabolism. It inhibits insulin receptor catalytic activity, and acts also at a more distal step, i.e. sterol regulatory element binding protein-1c maturation, which effect is predominant under short-term inhibition of Grb14 expression. |
| Databáze: | OpenAIRE |
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