FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress
| Autor: | Zhiwen Yu, Khajag Koulajian, Tony K.T. Lam, Adria Giacca, Roger Gutierrez-Juarez, Andrei I. Oprescu, Sonia M. Najjar, Deling Li, Alexander Ivovic, Jamel El-Benna, Jay Dewald, Laura Stavar, Robert Mckay, Toyoyoshi Uchida, Sandra Pereira, C. Andrew Haber, David N. Brindley, I. George Fantus, Thomas A. Bowman, Sanjay Bhanot, Yusaku Mori, Edward Park, Ping Han |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Antioxidant Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment Type 2 diabetes Fatty Acids Nonesterified medicine.disease_cause Pathogenesis Insulin resistance In vivo Physiology (medical) Internal medicine medicine Animals Rats Wistar Protein Kinase C Protein kinase C NADPH oxidase biology NADPH Oxidases Articles medicine.disease Rats Oxidative Stress Glucose Endocrinology Liver biology.protein Female Insulin Resistance Oxidative stress |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 307:E34-E46 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-l-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47phox(marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling. |
| Databáze: | OpenAIRE |
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