Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin.
Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Hepatic SREBP-1c is nutritionally regulated, and its sustained activation causes hepatic steatosis and insulin resistance. Although regulation of SREBP-1c is known to occur at the transcriptional level, the precise mechanism by which insulin signaling activates SREBP-1c promoter remains to be elucidated. Here we show that protein kinase C beta (PKCbeta) is a key mediator of insulin-mediated activation of hepatic SREBP-1c and its target lipogenic genes. Activation of SREBP-1c in the liver of refed mice was suppressed by either adenoviral RNAi-mediated knockdown or dietary administration of a specific inhibitor of protein kinase C beta. The effect of PKCbeta inhibition was cancelled in insulin depletion by streptozotocin (STZ) treatment of mice. Promoter analysis indicated that PKCbeta activates SREBP-1c promoter through replacement of Sp3 by Sp1 for binding to the GC box in the sterol regulatory element (SRE) complex, a key cis-element of SREBP-1c promoter. Knockdown of Sp proteins demonstrated that Sp3 and Sp1 play reciprocally negative and positive roles in nutritional regulation of SREBP-1c, respectively. This new understanding of PKCbeta involvement in nutritional regulation of SREBP-1c activation provides a new aspect of PKCbeta inhibition as a potential therapeutic target for diabetic complications.
Yamamoto
Takashi
T
Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Watanabe
Kazuhisa
K
Inoue
Noriyuki
N
Nakagawa
Yoshimi
Y
Ishigaki
Naomi
N
Matsuzaka
Takashi
T
Takeuchi
Yoshinori
Y
Kobayashi
Kazuto
K
Yatoh
Shigeru
S
Takahashi
Akimitsu
A
Suzuki
Hiroaki
H
Yahagi
Naoya
N
Gotoda
Takanari
T
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D007328:Insulin; D007527:Isoenzymes; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051744:Protein Kinase C-epsilon