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Papers In Press, published online ahead of print February 6, 2009
J. Lipid Res., doi:10.1194/jlr.M800520-JLR200
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Internal Medicine, James A. Haley Veterans Hospital, Tampa, Florida 33612
Corresponding Author: 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 lipids in liver are important components of obesity, but their pathogenesis and inter-relationships between muscle and liver are uncertain. Here, we studied two murine obesity models, moderate high-fat-feeding and heterozygous muscle-specific PKC-lambda 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 NFkappaB, 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 obesity models, inhibition of hepatic aPKC by adenovirally-mediated expression of kinase-inactive aPKC markedly diminished diet/insulin-dependent activation of hepatic SREBP-1c and NFkappaB, and concomitantly improved hepatosteatosis, hypertriglyceridemia and hyperglycemia. Moreover, in high-fat-fed mice, hyperinsulinemia and impairments in insulin signaling to IRS-1-dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle were largely reversed. Thus, in obesity, conserved hepatic aPKC-dependent activation of SREBP-1c and NFkappaB 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.
Revised on January 16, 2009
Accepted on February 5, 2009
Critical role of atypical protein kinase C in activating hepatic SREBP-1c and NF
B in obesity
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