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Submitted on November 29, 2005
Accepted on March 7, 2006
by Adenovirus-transduced siRNA Improves Hepatic Gluconeogenesis and Lipid Homeostasis in db/db Mice
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536; Department of Medicine and Department of Microbiology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80010
* To whom correspondence should be addressed. E-mail: JianhuaShao{at}uky.edu.
CCAAT/enhancer-binding protein 
(C/EBP) is a member of the basic leucine zipper transcription factor family and regulates expression of several enzymes in the liver that control glucose and lipid metabolism. Using adenovirus (Ad)-transduced siRNA against C/EBP, endogenous liver C/EBP protein was knocked down by 70-80% in 8- week old wild-type (WT) and db/db mice. In WT mice, fasting blood glucose concentrations were reduced 
24% without changes in plasma free fatty acid (FFA) and triglycerides, when compared with LacZ adenovirus-treated control mice. Ad-C/EBP siRNA treatment nearly normalized fasting glucose and significantly reduced plasma insulin and FFA content even though there is no elevation of C/EBP protein in the livers of db/db mice. In parallel with the changes in glucose levels, hepatic glucose production was significantly reduced in C/EBP siRNA treated WT and db/db mice. mRNA levels of phyosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and liver glycogen synthase were decreased in the C/EBP siRNA treated WT and db/db mice. Interestingly, the magnitude of reduction in these enzymes was more profound in db/db mice. C/EBP siRNA also decreased mRNA levels of PGC-1 in both the WT and the db/db mice, but reduced CREB only in WT and did not alter HNF4 and CBP/p300 expression. Expression of genes involved in lipogenesis, such as fatty acid synthase, acetyl-CoA carboxylase and sterol regulatory element-binding protein-1c (SREBP1c) was robustly suppressed in the C/EBP siRNA treated db/db mice. Taken together, these results indicate that C/EBP plays an important role in maintaining glucose and lipid homeostasis in the liver.
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