Elevated circulating free fatty acids (FFA) cause hepatic insulin resistance; however, the mechanisms for this process are incompletely understood. The objective of the studies in the thesis was to examine whether protein kinase C (PKC)-delta (d), oxidative stress, and the serine kinase IkBa kinase (IKK) B are causally involved in FFA-induced hepatic insulin resistance. To test this, we infused rats with lipid with or without inhibitors of the aforementioned factors for 7h, during the last 2h of which a hyperinsulinemic-euglycemic clamp was performed. In Study 1, inhibition of hepatic PKC-d using antisense oligonucleotide prevented FFA-induced membrane translocation of PKC-d, which is a marker of its activation, in parallel with prevention of lipid-induced hepatic insulin resistance, without affecting lipid-induced peripheral insulin resistance. These results implicate PKC-d as a causal mediator of FFA-induced hepatic insulin resistance. In Study 2, the antioxidant N-acetyl-L-cysteine (NAC) prevented lipid-induced hepatic insulin resistance in conjunction with reversal of lipid-induced increase in markers of IKKB and c-Jun NH2-terminal kinase 1 (JNK1) activation, and of impairment of insulin signaling, without affecting PKC-d membrane translocation and increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) induced by lipid infusion. These findings suggested that oxidative stress is a causal mediator of lipid-induced hepatic insulin resistance upstream of IKKB and JNK1, and potentially downstream of PKC-d and p38 MAPK. In Study 3, sodium salicylate, an IKKB inhibitor, prevented FFA-induced hepatic insulin resistance via restoration of hepatic insulin signaling, thus implicating IKKB as a causal factor in the process. Together, the results from these studies demonstrate that PKC-d, oxidative stress, and IKKB are causally involved in FFA-induced hepatic insulin resistance and suggest that the sequence for the process is: FFA -> PKC-d -> oxidative stress -> IKKB -> impaired hepatic insulin signaling.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/11242 |
| Date | 01 August 2008 |
| Creators | Park, Kyu Yol Edward |
| Contributors | Giacca, Adria |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
| Format | 2706504 bytes, application/pdf |
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