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Knocking Down Liver CCAAT/Enhancer-Binding Protein by Adenovirus-Transduced Silent Interfering Ribonucleic Acid Improves Hepatic Gluconeogenesis and Lipid Homeostasis in db/db Mice

Graduate Center for Nutritional Sciences (L.Q., H.Y., J.Sh.), University of Kentucky, Lexington, Kentucky 40536; and Departments of Medicine (P.S.M.) and Microbiology (J.Sc.), University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80010

Address all correspondence and requests for reprints to: Jianhua Shao, M.D., Ph.D., Graduate Center for Nutritional Sciences, University of Kentucky, 900 South Limestone, Lexington, Kentucky 40536-0200. 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-transduced silent interfering (si)RNA against C/EBP, endogenous liver C/EBP protein was knocked down by 70–80% in 8-wk-old wild-type (WT) and db/db mice. In WT mice, fasting blood glucose concentrations were reduced approximately 24% without changes in plasma free fatty acid 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 free fatty acid content, even though there was 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, glucose-6-phosphatase, 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 proliferator activator protein- coactivator-1 in both the WT and db/db mice but reduced cAMP response element-binding protein only in WT and did not alter hepatic nuclear factor-4 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 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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