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FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress.

Abstract
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 p47(phox) (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.
AuthorsSandra Pereira, Edward Park, Yusaku Mori, C Andrew Haber, Ping Han, Toyoyoshi Uchida, Laura Stavar, Andrei I Oprescu, Khajag Koulajian, Alexander Ivovic, Zhiwen Yu, Deling Li, Thomas A Bowman, Jay Dewald, Jamel El-Benna, David N Brindley, Roger Gutierrez-Juarez, Tony K T Lam, Sonia M Najjar, Robert A McKay, Sanjay Bhanot, I George Fantus, Adria Giacca
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 307 Issue 1 Pg. E34-46 (Jul 01 2014) ISSN: 1522-1555 [Electronic] United States
PMID24824652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2014 the American Physiological Society.
Chemical References
  • Fatty Acids, Nonesterified
  • NADPH Oxidases
  • protein kinase C gamma
  • Protein Kinase C
  • Glucose
Topics
  • Animals
  • Fatty Acids, Nonesterified (blood)
  • Female
  • Glucose (metabolism)
  • Insulin Resistance (physiology)
  • Liver (metabolism)
  • NADPH Oxidases (metabolism)
  • Oxidative Stress (physiology)
  • Protein Kinase C (metabolism)
  • Rats
  • Rats, Wistar

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