Metformin induces Rab4 through AMPK and modulates GLUT4 translocation in skeletal muscle cells
| Autor: | Jung Ok Lee, Sun Hwa Park, Soo Kyung Lee, Jin Hee Jung, Ga Young You, Su Jin Kim, Kyung Ok Uhm, Ji Hae Kim, Hyeon Soo Kim |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
endocrine system diseases Physiology Glucose uptake Clinical Biochemistry Biology Cell Line Mice Phosphoserine Internal medicine medicine Animals Humans Insulin Myocyte RNA Messenger Phosphorylation Muscle Skeletal Promoter Regions Genetic Protein kinase B Protein Kinase C Muscle Cells Glucose Transporter Type 4 rab4 GTP-Binding Proteins Adenylate Kinase nutritional and metabolic diseases Skeletal muscle AMPK Cell Biology Ribonucleotides Aminoimidazole Carboxamide Metformin Protein Structure Tertiary Protein Transport medicine.anatomical_structure Endocrinology Gene Expression Regulation biology.protein Mutant Proteins hormones hormone substitutes and hormone antagonists GLUT4 HeLa Cells Protein Binding Signal Transduction medicine.drug |
| Zdroj: | Journal of Cellular Physiology. 226:974-981 |
| ISSN: | 0021-9541 |
| DOI: | 10.1002/jcp.22410 |
| Popis: | Metformin is a major oral anti-diabetic drug and is known as an insulin sensitizer. However, the mechanism by which metformin acts is unclear. In this study, we found that AICAR, an AMPK activator, and metformin increased the expression of Rab4 mRNA and protein levels in skeletal muscle C2C12 cells. The promoter activity of Rab4 was increased by metformin in an AMPK-dependent manner. Metformin stimulated the phosphorylation of AS160, Akt substrate, and Rab GTPase activating protein (GAP), and also increased the phosphorylation of PKC-zeta, which is a critical molecule for glucose uptake. Knockdown of AMPK blocked the metformin-induced phosphorylation of AS160/PKC-zeta. In addition, a colorimetric absorbance assay showed that insulin-induced translocation of GLUT4 was suppressed in Rab4 knockdown cells. Moreover, Rab4 interacted with PKC-zeta but not with GLUT4. The C-terminal-deleted Rab4 mutant, Rab4ΔCT, showed diffuse sub-cellular localization, while wild-type Rab4 localized exclusively to the perinuclear membrane. Unlike Rab4ΔCT, wild-type Rab4 co-localized with PKC-zeta. Together, these results demonstrate that metformin induces Rab4 expression via AMPK-AS160-PKC-zeta and modulates insulin-mediated GLUT4 translocation. |
| Databáze: | OpenAIRE |
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