The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity
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 be...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2009-06-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520308117 |
| _version_ | 1818735008154648576 |
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| author | Mini P. Sajan Mary L. Standaert Sonali Nimal Usha Varanasi Tina Pastoor Stephen Mastorides Ursula Braun Michael Leitges Robert V. Farese |
| author_facet | Mini P. Sajan Mary L. Standaert Sonali Nimal Usha Varanasi Tina Pastoor Stephen Mastorides Ursula Braun Michael Leitges Robert V. Farese |
| author_sort | Mini P. Sajan |
| collection | DOAJ |
| description | 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-λ 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 NFκB (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 NFκB, 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 NFκB 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. |
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| format | Article |
| id | doaj.art-cbd0e4503c614e25a7cc9521df278c5a |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T00:14:25Z |
| publishDate | 2009-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-cbd0e4503c614e25a7cc9521df278c5a2022-12-21T21:27:33ZengElsevierJournal of Lipid Research0022-22752009-06-0150611331145The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesityMini P. Sajan0Mary L. Standaert1Sonali Nimal2Usha Varanasi3Tina Pastoor4Stephen Mastorides5Ursula Braun6Michael Leitges7Robert V. Farese8James A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLJames A. Haley Veterans Hospital, Tampa, FL; Roskamp Institute, Sarasota, FL; Biotechnology Centre of Oslo, Oslo, Norway; College of Medicine, University of South Florida, Tampa, FLObesity 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-λ 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 NFκB (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 NFκB, 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 NFκB 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.http://www.sciencedirect.com/science/article/pii/S0022227520308117atypical protein kinase Chigh fat feedinghyperlipidemiainsulininsulin resistanceIRS-1 |
| spellingShingle | Mini P. Sajan Mary L. Standaert Sonali Nimal Usha Varanasi Tina Pastoor Stephen Mastorides Ursula Braun Michael Leitges Robert V. Farese The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity Journal of Lipid Research atypical protein kinase C high fat feeding hyperlipidemia insulin insulin resistance IRS-1 |
| title | The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity |
| title_full | The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity |
| title_fullStr | The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity |
| title_full_unstemmed | The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity |
| title_short | The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFκB in obesity |
| title_sort | critical role of atypical protein kinase c in activating hepatic srebp 1c and nfκb in obesity |
| topic | atypical protein kinase C high fat feeding hyperlipidemia insulin insulin resistance IRS-1 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520308117 |
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