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Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones

Abstract

We have previously shown that expression of the transcription factor ARNT/HIF1beta is reduced in islets of humans with type 2 diabetes. We have now found that ARNT is also reduced in livers of diabetics. To study the functional effect of its reduction, we created mice with liver-specific ablation (L-ARNT KO) using ARNT loxP mice and adenoviral-mediated delivery of Cre. L-ARNT KO mice had normal blood glucose but increased fed insulin levels. These mice also exhibited features of type 2 diabetes with increased hepatic gluconeogenesis, increased lipogenic gene expression, and low serum beta-hydroxybutyrate. These effects appear to be secondary to increased expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha), farnesoid X receptor (FXR), and sterol response element-binding protein 1c (SREBP-1c) and a reduction in phosphorylation of AMPK without changes in the expression of enzymes in ketogenesis, fatty acid oxidation, or FGF21. These results demonstrate that a deficiency of ARNT action in the liver, coupled with that in beta cells, could contribute to the metabolic phenotype of human type 2 diabetes.

Type Journal
ISBN 1932-7420 (Electronic)
Authors Wang, X. L.; Suzuki, R.; Lee, K.; Tran, T.; Gunton, J. E.; Saha, A. K.; Patti, M. E.; Goldfine, A.; Ruderman, N. B.; Gonzalez, F. J.; Kahn, C. R.;
Garvan Authors Prof Jenny Gunton
Publisher Name CELL METAB
Published Date 2009-01-01 00:00:00
Published Volume 9
Published Issue 5
Published Pages 428-39
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19416713
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10280_10389/09 Wang CM.pdf