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PMID: 12975478 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity.

The Journal of clinical investigation ·Vol. 112 ·No. 6 ·2003-09-00 ·Pages 935-44

Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K, Hayashi Y, Iguchi H, Matsuki Y, Hiramatsu R, Shimano H, Yamada N, Ohno S, Kasuga M, Noda T

Abstract

PKClambda is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKClambda specifically in the liver (L-lambdaKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element-binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-lambdaKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKClambda and was mimicked by overexpression of WT PKClambda. Restoration of PKClambda expression in the liver of L-lambdaKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.

MeSH Terms
Animals Blood Glucose/metabolism CCAAT-Enhancer-Binding Proteins/genetics,metabolism Cells, Cultured DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation Hepatocytes/cytology,metabolism Humans Insulin/metabolism Isoenzymes Lipid Metabolism Liver/chemistry,physiology Male Mice Mice, Knockout Phenotype Protein Kinase C/genetics,metabolism Rats Sterol Regulatory Element Binding Protein 1 Tissue Distribution Transcription Factors/metabolism
Chemicals
Blood Glucose CCAAT-Enhancer-Binding Proteins DNA-Binding Proteins Insulin Isoenzymes SREBF1 protein, human Srebf1 protein, mouse Srebf1 protein, rat Sterol Regulatory Element Binding Protein 1 Transcription Factors protein kinase C eta Protein Kinase C protein kinase C lambda
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Matsumoto Michihiro
Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Ogawa Wataru
Akimoto Kazunori
Inoue Hiroshi
Miyake Kazuaki
Furukawa Kensuke
Hayashi Yoshitake
Iguchi Haruhisa
Matsuki Yasushi
Hiramatsu Ryuji
Shimano Hitoshi
Yamada Nobuhiro
Ohno Shigeo
Kasuga Masato
Noda Tetsuo
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI18816
Published
2003-09-00
Pages
935-44
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC193669
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI18816 PMC Full Text View journal details
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