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Title: Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase C{epsilon}

Abstract

It is known that free fatty acid (FFA) contributes to the development of insulin resistance and type2 diabetes. However, the underlying mechanism in FFA-induced insulin resistance is still unclear. In the present investigation we have demonstrated that palmitate significantly (p < 0.001) inhibited insulin-stimulated phosphorylation of PDK1, the key insulin signaling molecule. Consequently, PDK1 phosphorylation of plasma membrane bound PKC{epsilon} was also inhibited. Surprisingly, phosphorylation of cytosolic PKC{epsilon} was greatly stimulated by palmitate; this was then translocated to the nuclear region and associated with the inhibition of insulin receptor (IR) gene transcription. A PKC{epsilon} translocation inhibitor peptide, {epsilon}V1, suppressed this inhibitory effect of palmitate, suggesting requirement of phospho-PKC{epsilon} migration to implement palmitate effect. Experimental evidences indicate that phospho-PKC{epsilon} adversely affected HMGA1. Since HMGA1 regulates IR promoter activity, expression of IR gene was impaired causing reduction of IR on cell surface and that compromises with insulin sensitivity.

Authors:
 [1];  [2];  [1];  [3]
  1. Molecular Endocrinology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032 (India)
  2. Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati University, Santiniketan 731235 (India)
  3. Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati University, Santiniketan 731235 (India). E-mail: smrbhattacharya@gmail.com
Publication Date:
OSTI Identifier:
20991367
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 357; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2007.03.183; PII: S0006-291X(07)00659-6; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARBOXYLIC ACIDS; CELL MEMBRANES; GENES; INHIBITION; INSULIN; PEPTIDES; PHOSPHORYLATION; PROMOTERS; RECEPTORS; SENSITIVITY; TRANSCRIPTION; TRANSLOCATION

Citation Formats

Dey, Debleena, Bhattacharya, Anirban, Roy, SibSankar, and Bhattacharya, Samir. Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase C{epsilon}. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.03.183.
Dey, Debleena, Bhattacharya, Anirban, Roy, SibSankar, & Bhattacharya, Samir. Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase C{epsilon}. United States. doi:10.1016/j.bbrc.2007.03.183.
Dey, Debleena, Bhattacharya, Anirban, Roy, SibSankar, and Bhattacharya, Samir. Fri . "Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase C{epsilon}". United States. doi:10.1016/j.bbrc.2007.03.183.
@article{osti_20991367,
title = {Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase C{epsilon}},
author = {Dey, Debleena and Bhattacharya, Anirban and Roy, SibSankar and Bhattacharya, Samir},
abstractNote = {It is known that free fatty acid (FFA) contributes to the development of insulin resistance and type2 diabetes. However, the underlying mechanism in FFA-induced insulin resistance is still unclear. In the present investigation we have demonstrated that palmitate significantly (p < 0.001) inhibited insulin-stimulated phosphorylation of PDK1, the key insulin signaling molecule. Consequently, PDK1 phosphorylation of plasma membrane bound PKC{epsilon} was also inhibited. Surprisingly, phosphorylation of cytosolic PKC{epsilon} was greatly stimulated by palmitate; this was then translocated to the nuclear region and associated with the inhibition of insulin receptor (IR) gene transcription. A PKC{epsilon} translocation inhibitor peptide, {epsilon}V1, suppressed this inhibitory effect of palmitate, suggesting requirement of phospho-PKC{epsilon} migration to implement palmitate effect. Experimental evidences indicate that phospho-PKC{epsilon} adversely affected HMGA1. Since HMGA1 regulates IR promoter activity, expression of IR gene was impaired causing reduction of IR on cell surface and that compromises with insulin sensitivity.},
doi = {10.1016/j.bbrc.2007.03.183},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 357,
place = {United States},
year = {Fri Jun 01 00:00:00 EDT 2007},
month = {Fri Jun 01 00:00:00 EDT 2007}
}