Open Access Highly Accessed Research article

The transcriptomic signature of fasting murine liver

Milka Sokolović12, Aleksandar Sokolović1, Diederik Wehkamp3, Emiel Ver Loren van Themaat3, Dirk R de Waart1, Lisa A Gilhuijs-Pederson3, Yuri Nikolsky4, Antoine HC van Kampen3, Theodorus BM Hakvoort1 and Wouter H Lamers1*

Author Affiliations

1 AMC Liver Center, Academic Medical Center, University of Amsterdam, The Netherlands

2 Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands

3 Bioinformatics Laboratory, Academic Medical Center, University of Amsterdam, The Netherlands

4 GeneGo, Inc., St. Joseph, MI, USA

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BMC Genomics 2008, 9:528  doi:10.1186/1471-2164-9-528

Published: 6 November 2008

Abstract

Background

The contribution of individual organs to the whole-body adaptive response to fasting has not been established. Hence, gene-expression profiling, pathway, network and gene-set enrichment analysis and immunohistochemistry were carried out on mouse liver after 0, 12, 24 and 72 hours of fasting.

Results

Liver wet weight had declined ~44, ~5, ~11 and ~10% per day after 12, 24, 48 and 72 hours of fasting, respectively. Liver structure and metabolic zonation were preserved. Supervised hierarchical clustering showed separation between the fed, 12–24 h-fasted and 72 h-fasted conditions. Expression profiling and pathway analysis revealed that genes involved in amino-acid, lipid, carbohydrate and energy metabolism responded most significantly to fasting, that the response peaked at 24 hours, and had largely abated by 72 hours. The strong induction of the urea cycle, in combination with increased expression of enzymes of the tricarboxylic-acid cycle and oxidative phosphorylation, indicated a strong stimulation of amino-acid oxidation peaking at 24 hours. At this time point, fatty-acid oxidation and ketone-body formation were also induced. The induction of genes involved in the unfolded-protein response underscored the cell stress due to enhanced energy metabolism. The continuous high expression of enzymes of the urea cycle, malate-aspartate shuttle, and the gluconeogenic enzyme Pepck and the re-appearance of glycogen in the pericentral hepatocytes indicate that amino-acid oxidation yields to glucose and glycogen synthesis during prolonged fasting.

Conclusion

The changes in liver gene expression during fasting indicate that, in the mouse, energy production predominates during early fasting and that glucose production and glycogen synthesis become predominant during prolonged fasting.