PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity.
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.
Matsumoto
Michihiro
M
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
W
Akimoto
Kazunori
K
Inoue
Hiroshi
H
Miyake
Kazuaki
K
Furukawa
Kensuke
K
Hayashi
Yoshitake
Y
Iguchi
Haruhisa
H
Matsuki
Yasushi
Y
Hiramatsu
Ryuji
R
Shimano
Hitoshi
H
Yamada
Nobuhiro
N
Ohno
Shigeo
S
Kasuga
Masato
M
Noda
Tetsuo
T
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007527:Isoenzymes; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D000099293:Protein Kinase C-lambda
D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D007527:Isoenzymes; D011493:Protein Kinase C; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000099293:Protein Kinase C-lambda; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; C081975:protein kinase C eta