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The transcriptomic signature of fasting murine liver.

Sokolović M, Sokolović A, Wehkamp D, Ver Loren van Themaat E, de Waart DR, Gilhuijs-Pederson LA, Nikolsky Y, van Kampen AH, Hakvoort TB, Lamers WH - BMC Genomics (2008)

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: AMC Liver Center, Academic Medical Center, University of Amsterdam, The Netherlands. m.sokolovic@amc.uva.nl

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 approximately 44, approximately 5, approximately 11 and approximately 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.

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The unfolded-protein response in fasting. The network was generated and linked with available experimental data in the MetaCore™ suite. Nodes with red or blue circles in top right corner of the network objects, represent up- or down-regulation, respectively, with the shade indicating the intensity of the change. Detailed legend for MC networks is provided in Additional file 3.
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Figure 10: The unfolded-protein response in fasting. The network was generated and linked with available experimental data in the MetaCore™ suite. Nodes with red or blue circles in top right corner of the network objects, represent up- or down-regulation, respectively, with the shade indicating the intensity of the change. Detailed legend for MC networks is provided in Additional file 3.

Mentions: Interestingly, the 3 top-scoring processes obtained from a biological-process enrichment analysis all belonged to the unfolded-protein response (endoplasmic reticulum (ER) stress). To present the relevant data in a single figure, we created a network using the shortest-path algorithm (Figure 10). The resulting network provides links based on the known interaction data between the nodes from the query data set, and also between the nodes that regulate the given genes or metabolites. It shows 8 heat-shock and 6 other proteins, all upregulated 1.5–2.5 fold, indicating upregulation of this stress-response pathway in fasted liver. Downstream of the ER stress pathway, proteasome degradation was also upregulated, but again only after 24 hours of fasting (Figure 11). A list of these and some additional genes regulated in the ER stress and proteasome degradation, with their change level, is shown in Table 3.


The transcriptomic signature of fasting murine liver.

Sokolović M, Sokolović A, Wehkamp D, Ver Loren van Themaat E, de Waart DR, Gilhuijs-Pederson LA, Nikolsky Y, van Kampen AH, Hakvoort TB, Lamers WH - BMC Genomics (2008)

The unfolded-protein response in fasting. The network was generated and linked with available experimental data in the MetaCore™ suite. Nodes with red or blue circles in top right corner of the network objects, represent up- or down-regulation, respectively, with the shade indicating the intensity of the change. Detailed legend for MC networks is provided in Additional file 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2588605&req=5

Figure 10: The unfolded-protein response in fasting. The network was generated and linked with available experimental data in the MetaCore™ suite. Nodes with red or blue circles in top right corner of the network objects, represent up- or down-regulation, respectively, with the shade indicating the intensity of the change. Detailed legend for MC networks is provided in Additional file 3.
Mentions: Interestingly, the 3 top-scoring processes obtained from a biological-process enrichment analysis all belonged to the unfolded-protein response (endoplasmic reticulum (ER) stress). To present the relevant data in a single figure, we created a network using the shortest-path algorithm (Figure 10). The resulting network provides links based on the known interaction data between the nodes from the query data set, and also between the nodes that regulate the given genes or metabolites. It shows 8 heat-shock and 6 other proteins, all upregulated 1.5–2.5 fold, indicating upregulation of this stress-response pathway in fasted liver. Downstream of the ER stress pathway, proteasome degradation was also upregulated, but again only after 24 hours of fasting (Figure 11). A list of these and some additional genes regulated in the ER stress and proteasome degradation, with their change level, is shown in Table 3.

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: AMC Liver Center, Academic Medical Center, University of Amsterdam, The Netherlands. m.sokolovic@amc.uva.nl

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 approximately 44, approximately 5, approximately 11 and approximately 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.

Show MeSH
Related in: MedlinePlus