Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and NFκB in rodent diabetic liver and relationships to hyperlipidemia and insulin resistance
| Autor: | Sajan, M. P., Standaert, M. L., Rivas, J., Miura, A., Kanoh, Y., Soto, J., Taniguchi, C.M., Kahn, C.R., Farese, R.V. |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Blood Glucose
Male Analysis of Variance Muscles Blotting Western NF-kappa B Electrophoretic Mobility Shift Assay Hyperlipidemias Article Rats Disease Models Animal Phosphatidylinositol 3-Kinases Cholesterol Liver Diabetes Mellitus Insulin Receptor Substrate Proteins Animals Insulin Resistance Rats Wistar Sterol Regulatory Element Binding Protein 1 Protein Kinase C Triglycerides |
| Popis: | Previous findings in rodents used as a model of diabetes suggest that insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but, unexpectedly, conserved in liver, despite impaired hepatic protein kinase B (PKB/Akt) activation. Moreover, aPKC at least partly regulates two major transactivators: (1) hepatic sterol receptor binding protein-1c (SREBP-1c), which controls lipid synthesis; and (2) nuclear factor kappa B (NFkappaB), which promotes inflammation and systemic insulin resistance.In Goto-Kakizaki rats used as a model of type 2 diabetes, we examined: (1) whether differences in hepatic aPKC and PKB activation reflect differences in activation of IRS-1- and IRS-2-dependent phosphatidylinositol 3-kinase (PI3K); (2) whether hepatic SREBP-1c and NFkappaB are excessively activated by aPKC; and (3) metabolic consequences of excessive activation of hepatic aPKC, SREBP-1c and NFkappaB.In liver, as well as in muscle, IRS-2/PI3K activation by insulin was intact, whereas IRS-1/PI3K activation by insulin was impaired. Moreover, hepatic IRS-2 is known to control hepatic aPKC during insulin activation. Against this background, selective inhibition of hepatic aPKC by adenoviral-mediated expression of mRNA encoding kinase-inactive aPKC or short hairpin RNA targeting Irs2 mRNA and partially depleting hepatic IRS-2 diminished hepatic SREBP-1c production and NFkappaB activities, concomitantly improving serum lipids and insulin signalling in muscle and liver. Similar improvements in SREBP-1c, NFkappaB and insulin signalling were seen in ob/ob mice following inhibition of hepatic aPKC.In diabetic rodent liver, diminished PKB activation may largely reflect impaired IRS-1/PI3K activation, while conserved aPKC activation reflects retained IRS-2/PI3K activity. Hepatic aPKC may also contribute importantly to excessive SREPB-1c and NFkappaB activities. Excessive hepatic aPKC-dependent activation of SREBP-1c and NFkappaB may contribute importantly to hyperlipidaemia and systemic insulin resistance. |
| Databáze: | OpenAIRE |
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