| RRC ID |
68987
|
| 著者 |
Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda Y, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M.
|
| タイトル |
Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.
|
| ジャーナル |
Am J Physiol Endocrinol Metab
|
| Abstract |
Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.
|
| 巻・号 |
306(9)
|
| ページ |
E1065-76
|
| 公開日 |
2014-5-1
|
| DOI |
10.1152/ajpendo.00597.2012
|
| PII |
ajpendo.00597.2012
|
| PMID |
24619881
|
| MeSH |
Animals
Cells, Cultured
GTPase-Activating Proteins / metabolism
Gene Knockdown Techniques
Glucose / metabolism*
Glucose Transporter Type 4 / metabolism*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Insulin / pharmacology
Mice
Mice, Transgenic
Muscle Fibers, Skeletal / drug effects
Muscle Fibers, Skeletal / metabolism
Muscle, Skeletal / drug effects
Muscle, Skeletal / metabolism*
Protein Transport / drug effects
Protein Transport / genetics
|
| IF |
3.469
|
| リソース情報 |
| ヒト・動物細胞 |
C2C12(RCB0987) |
