title: Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cepsilon.
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 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.
authors: Molecular Endocrinology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India.
authors: Debleena
authors: D
authors: Dey
authors: Anirban
authors: A
authors: Bhattacharya
authors: Sibsankar
authors: S
authors: Roy
authors: Samir
authors: S
authors: Bhattacharya
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D025741:HMGA1a Protein / Q000378:metabolism*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D005230:Fatty Acids, Nonesterified; D025741:HMGA1a Protein; D011972:Receptor, Insulin; D051744:Protein Kinase C-epsilon