Inhibition of insulin receptor gene expression and insulin signaling by fatty acid: interplay of PKC isoforms therein.
Fatty acids are known to play a key role in promoting the loss of insulin sensitivity causing insulin resistance and type 2 diabetes. However, underlying mechanism involved here is still unclear. Incubation of rat skeletal muscle cells with palmitate followed by I(125)- insulin binding to the plasma membrane receptor preparation demonstrated a two-fold decrease in receptor occupation. In searching the cause for this reduction, we found that palmitate inhibition of insulin receptor (IR) gene expression effecting reduced amount of IR protein in skeletal muscle cells. This was followed by the inhibition of insulin-stimulated IRbeta tyrosine phosphorylation that consequently resulted inhibition of insulin receptor substrate 1 (IRS 1) and IRS 1 associated phosphatidylinositol-3 kinase (PI3 Kinase), phosphoinositide dependent kinase-1 (PDK 1) phosphorylation. PDK 1 dependent phosphorylation of PKCzeta and Akt/PKB were also inhibited by palmitate. Surprisingly, although PKCepsilon phosphorylation is PDK1 dependent, palmitate effected its constitutive phosphorylation independent of PDK1. Time kinetics study showed translocation of palmitate induced phosphorylated PKCepsilon from cell membrane to nuclear region and its possible association with the inhibition of IR gene transcription. Our study suggests one of the pathways through which fatty acid can induce insulin resistance in skeletal muscle cell.
Dey
Debleena
D
Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati University, Santiniketan, India.
Mukherjee
Mohua
M
Basu
Dipanjan
D
Datta
Malabika
M
Roy
Sib Sankar
SS
Bandyopadhyay
Arun
A
Bhattacharya
Samir
S
D000818:Animals; D005786:Gene Expression Regulation; D007329:Insulin Antagonists / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D007329:Insulin Antagonists; D007527:Isoenzymes; D010168:Palmitates; C497257:Prkce protein, rat; D011972:Receptor, Insulin; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon