| First Author | Dasgupta S | Year | 2011 |
| Journal | Biochim Biophys Acta | Volume | 1812 |
| Issue | 4 | Pages | 495-506 |
| PubMed ID | 21236337 | Mgi Jnum | J:169870 |
| Mgi Id | MGI:4943373 | Doi | 10.1016/j.bbadis.2011.01.001 |
| Citation | Dasgupta S, et al. (2011) Mechanism of lipid induced insulin resistance: activated PKCepsilon is a key regulator. Biochim Biophys Acta 1812(4):495-506 |
| abstractText | 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 PKCepsilon and reduced IR expression. We report here that central to this mechanism is the phosphorylation of PKCepsilon by FAs. Kinase dead mutant of PKCepsilon did not augment FA induced IRbeta downregulation indicating phosphorylation of PKCepsilon is crucial for FA induced IRbeta reduction. Investigation with insulin target cells showed that kinase independent phosphorylation of PKCepsilon by FA occurred through palmitoylation. Mutation at cysteine 276 and 474 residues in PKCepsilon suppressed this process indicating participation of these two residues in palmitoylation. Phosphorylation of PKCepsilon endowed it the ability to migrate to the nuclear region of insulin target cells. It was intriguing to search about how translocation of phosphorylated PKCepsilon occurred without having canonical nuclear localization signal (NLS). We found that F-actin recognized phospho-form of PKCepsilon 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. |
