| RRC ID |
39628
|
| 著者 |
Nakajima K, Yamauchi K, Shigematsu S, Ikeo S, Komatsu M, Aizawa T, Hashizume K.
|
| タイトル |
Selective attenuation of metabolic branch of insulin receptor down-signaling by high glucose in a hepatoma cell line, HepG2 cells.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
The effects of a high concentration of glucose on the insulin receptor-down signaling were investigated in human hepatoma (HepG2) cells in vitro to delineate the molecular mechanism of insulin resistance under glucose toxicity. Treatment of the cells with high concentrations of glucose (15-33 mm) caused phosphorylation of serine residues of the insulin receptor substrate 1 (IRS-1), leading to reduced electrophoretic mobility of it. The phosphorylation of IRS-1 with high glucose treatment was blocked only by protein kinase C (PKC) inhibitors. The high glucose treatment attenuated insulin-induced association of IRS-1 and phosphatidylinositol 3-kinase and insulin-stimulated phosphorylation of Akt. A metabolic effect of insulin, stimulation of glycogen synthesis, was also inhibited by the treatment. In contrast, insulin-induced association of Shc and Grb2 was not inhibited. Treatment of the cells with high glucose promoted the translocation of PKCepsilon and PKCdelta from the cytosol to the plasma membrane but not that of other PKC isoforms. Finally, PKCepsilon and PKCdelta directly phosphorylated IRS-1 under cell-free conditions. We conclude that a high concentration of glucose causes phosphorylation of IRS-1, leading to selective attenuation of metabolic signaling of insulin. PKCepsilon and PKCdelta are involved in the down-regulation of insulin signaling, and they may lie in a pathway regulating the phosphorylation of IRS-1.
|
| 巻・号 |
275(27)
|
| ページ |
20880-6
|
| 公開日 |
2000-7-7
|
| DOI |
10.1074/jbc.M905410199
|
| PII |
S0021-9258(19)79914-1
|
| PMID |
10764799
|
| MeSH |
Adaptor Proteins, Signal Transducing*
Adaptor Proteins, Vesicular Transport*
Carcinoma, Hepatocellular
Down-Regulation / drug effects
GRB2 Adaptor Protein
Glucose / pharmacology*
Glycogen / biosynthesis
Humans
Insulin Receptor Substrate Proteins
Isoenzymes / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoamino Acids / analysis
Phosphoproteins / metabolism
Phosphorylation
Protein Kinase C / metabolism
Protein Serine-Threonine Kinases / metabolism
Proteins / metabolism
Proto-Oncogene Proteins*
Proto-Oncogene Proteins c-akt
Receptor, Insulin / metabolism*
Shc Signaling Adaptor Proteins
Signal Transduction / drug effects*
Src Homology 2 Domain-Containing, Transforming Protein 1
Tumor Cells, Cultured
|
| IF |
4.238
|
| 引用数 |
80
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
