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.
Highlights
Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver
T1317 robustly activates the Sterol regulatory element-binding protein (SREBP)-1c promoter in pBP-1c550 and pBP1c550 (⌬sterol regulatory element (SRE) complex) constructs containing LXR response element (LXRE) but not in pBP-1c90 and pBP-1cTATA-Luc constructs
Activation of this minimal promoter by PMA was dose-dependently inhibited by GF 109203X (GFX), an inhibitor of protein kinase C (PKC), confirming that PMA activation of the SREBP-1c promoter was mediated by PKC (Fig. 2A)
Summary
Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Expression of PKCbeta, as well as PKCepsilon, dose-dependently activated the SREBP-1c promoter (Fig. 2C). Gel-shift assay focusing on the responsible 90 bp region demonstrated that nuclear extract from HepG2 cells treated with PMA exhibited a robust and consistent binding to the SRE complex probe (-92bp and -35bp) (Fig. 3A), whereas no signal was obtained from other probes to other sections of the SREBP-1c promoter (data not shown).
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