title: Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Watanabe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Inoue
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishigaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Takanari
authors.initials: T
authors.lastname: Gotoda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: 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
chemical_list: 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