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The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity.
- Source :
-
Journal of lipid research [J Lipid Res] 2009 Jun; Vol. 50 (6), pp. 1133-45. Date of Electronic Publication: 2009 Feb 06. - Publication Year :
- 2009
-
Abstract
- 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-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 (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 NFkappaB, 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 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.
- Subjects :
- Animals
Base Sequence
DNA Primers genetics
Dietary Fats administration & dosage
Disease Models, Animal
I-kappa B Kinase metabolism
Insulin blood
Insulin metabolism
Insulin Resistance
Isoenzymes deficiency
Isoenzymes genetics
Isoenzymes metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal metabolism
Obesity etiology
Obesity genetics
Protein Kinase C deficiency
Protein Kinase C genetics
RNA, Messenger genetics
RNA, Messenger metabolism
Signal Transduction
Sterol Regulatory Element Binding Protein 1 genetics
Liver metabolism
NF-kappa B metabolism
Obesity metabolism
Protein Kinase C metabolism
Sterol Regulatory Element Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2275
- Volume :
- 50
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 19202134
- Full Text :
- https://doi.org/10.1194/jlr.M800520-JLR200