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Journal of Lipid Research, Vol. 50, 1133-1145, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFB in obesity

Mini P. Sajan^*,**, Mary L. Standaert^*, Sonali Nimal, Usha Varanasi, Tina Pastoor, Stephen Mastorides^*, Ursula Braun^**, Michael Leitges and Robert V. Farese^1,*,,**

^* James A. Haley Veterans Hospital, Tampa, FL
Roskamp Institute, Sarasota, FL
Biotechnology Centre of Oslo, Oslo, Norway
^** College of Medicine, University of South Florida, Tampa, FL

This work was supported by funds from the Department of Veterans Affairs Merit Review Program and the National Institutes of Health DK-38079 (R. V. F.), and by the Deutsche Forschungsgemeinschaft Sta314/2-1 and KE246/7-2 (M. L.).

Published, JLR Papers in Press, February 6, 2009.

¹ To whom correspondence should be addressed. e-mail: rfarese{at}health.usf.edu

Obesity is frequently associated with systemic insulin resistance, glucose intolerance, and hyperlipidemia. Impaired insulin action in muscle and paradoxical diet/insulin-dependent overproduction of hepatic lipids are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. We studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC- knockout, in both of which insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but conserved in liver. In both models, activation of hepatic sterol receptor element binding protein-1c (SREBP-1c) and NFB (nuclear factor-kappa B), major regulators of hepatic lipid synthesis and systemic insulin resistance, was chronically increased in the fed state. In support of a critical mediatory role of aPKC, in both models, inhibition of hepatic aPKC by adenovirally mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFB, and concomitantly improved hepatosteatosis, hypertriglyceridemia, hyperinsulinemia, and hyperglycemia. Moreover, in high-fat–fed mice, impaired insulin signaling to IRS-1–dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed. In obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFB contributes importantly to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance. Accordingly, hepatic aPKC is a potential target for treating obesity-associated abnormalities.

Supplementary key words atypical protein kinase C • high fat feeding • hyperlipidemia • insulin • insulin resistance • IRS-1 • IRS-2 • liver • muscle • NFB • obesity • phosphatidylinositol 3-kinase • SREBP-1c • type 2 diabetes

Abbreviations: aPKC, atypical protein kinase C; SREBP-1c, hepatic sterol receptor element binding protein-1c; KO, knockout; NFB, nuclear factor-kappa B

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