title: Mechanism of lipid induced insulin resistance: activated PKCε is a key regulator.
abstract: Fatty acids (FAs) are known to impair insulin signaling in target cells. Accumulating evidences suggest that one of the major sites of FAs adverse effect is insulin receptor (IR). However, the underlying mechanism is yet unclear. An important clue was indicated in leptin receptor deficient (db/db) diabetic mice where increased circulatory FAs was coincided with phosphorylated PKCε and reduced IR expression. We report here that central to this mechanism is the phosphorylation of PKCε by FAs. Kinase dead mutant of PKCε did not augment FA induced IRβ downregulation indicating phosphorylation of PKCε is crucial for FA induced IRβ reduction. Investigation with insulin target cells showed that kinase independent phosphorylation of PKCε by FA occurred through palmitoylation. Mutation at cysteine 276 and 474 residues in PKCε suppressed this process indicating participation of these two residues in palmitoylation. Phosphorylation of PKCε endowed it the ability to migrate to the nuclear region of insulin target cells. It was intriguing to search about how translocation of phosphorylated PKCε occurred without having canonical nuclear localization signal (NLS). We found that F-actin recognized phospho-form of PKCε and chaperoned it to the nuclear region where it interact with HMGA1 and Sp1, the transcription regulator of IR and HMGA1 gene respectively and impaired HMGA1 function. This resulted in the attenuation of HMGA1 driven IR transcription that compromised insulin signaling and sensitivity.
authors.affiliation: Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati University, Santiniketan 731235, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Sushmita
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Sudipta
authors.initials: S
authors.lastname: Maitra
authors.forename: Durba
authors.initials: D
authors.lastname: Pal
authors.forename: Subeer S
authors.initials: SS
authors.lastname: Majumdar
authors.forename: Asis
authors.initials: A
authors.lastname: Datta
authors.forename: Samir
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019308:Palmitic Acid / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D005227:Fatty Acids; D024003:HMGA Proteins; D019308:Palmitic Acid; D011972:Receptor, Insulin; D051744:Protein Kinase C-epsilon