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Ensemble modeling of hepatic fatty acid metabolism with a synthetic glyoxylate shunt.
- Source :
-
Biophysical journal [Biophys J] 2010 Apr 21; Vol. 98 (8), pp. 1385-95. - Publication Year :
- 2010
-
Abstract
- The liver plays a central role in maintaining whole body metabolic and energy homeostasis by consuming and producing glucose and fatty acids. Glucose and fatty acids compete for hepatic substrate oxidation with regulation ensuring glucose is oxidized preferentially. Increasing fatty acid oxidation is expected to decrease lipid storage in the liver and avoid lipid-induced insulin-resistance. To increase hepatic lipid oxidation in the presence of glucose, we previously engineered a synthetic glyoxylate shunt into human hepatocyte cultures and a mouse model and showed that this synthetic pathway increases free fatty acid beta-oxidation and confers resistance to diet-induced obesity in the mouse model. Here we used ensemble modeling to decipher the effects of perturbations to the hepatic metabolic network on fatty acid oxidation and glucose uptake. Despite sampling of kinetic parameters using the most fundamental elementary reaction models, the models based on current metabolic regulation did not readily describe the phenotype generated by glyoxylate shunt expression. Although not conclusive, this initial negative result prompted us to probe unknown regulations, and malate was identified as inhibitor of hexokinase 2 expression either through direct or indirect actions. This regulation allows the explanation of observed phenotypes (increased fatty acid degradation and decreased glucose consumption). Moreover, the result is a function of pyruvate-carboxylase, mitochondrial pyruvate transporter, citrate transporter protein, and citrate synthase activities. Some subsets of these flux ratios predict increases in fatty acid and decreases in glucose uptake after glyoxylate expression, whereas others predict no change. Altogether, this work defines the possible biochemical space where the synthetic shunt will produce the desired phenotype and demonstrates the efficacy of ensemble modeling for synthetic pathway design.<br /> (Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Hep G2 Cells
Hepatocytes drug effects
Hepatocytes enzymology
Hexokinase antagonists & inhibitors
Humans
Kinetics
Liver drug effects
Liver enzymology
Malates pharmacology
Mice
Fatty Acids metabolism
Glyoxylates metabolism
Lipid Metabolism drug effects
Liver metabolism
Metabolic Networks and Pathways drug effects
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1542-0086
- Volume :
- 98
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biophysical journal
- Publication Type :
- Academic Journal
- Accession number :
- 20409457
- Full Text :
- https://doi.org/10.1016/j.bpj.2009.12.4308