Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cepsilon

• Published in: Biochemical and biophysical research communications Vol. 357; no. 2; pp. 474 - 479
• Main Authors: Dey, Debleena, Bhattacharya, Anirban, Roy, Sibsankar, Bhattacharya, Samir
• Format: Journal Article
• Language: English
• Published: United States 01.06.2007
• Subjects: Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified - administration & dosage; Gene Expression - drug effects; Gene Expression - physiology; HMGA1a Protein - metabolism; Humans; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Phosphorylation - drug effects; Protein Kinase C-epsilon - metabolism; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Transcription, Genetic - drug effects; Transcription, Genetic - physiology
• ISSN: 0006-291X

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 PKCepsilon was also inhibited. Surprisingly, phosphorylation of cytosolic PKCepsilon 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 PKCepsilon translocation inhibitor peptide, epsilonV1, suppressed this inhibitory effect of palmitate, suggesting requirement of phospho-PKCepsilon migration to implement palmitate effect. Experimental evidences indicate that phospho-PKCepsilon 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.