title: A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation.
abstract: Liver X receptor (LXR) agonists exert potent antiatherosclerotic actions but simultaneously induce excessive triglyceride (TG) accumulation in the liver. To obtain a detailed insight into the underlying mechanism of hepatic TG accumulation, we used a novel computational modeling approach called analysis of dynamic adaptations in parameter trajectories (ADAPT). We revealed that both input and output fluxes to hepatic TG content are considerably induced on LXR activation and that in the early phase of LXR agonism, hepatic steatosis results from only a minor imbalance between the two. It is generally believed that LXR-induced hepatic steatosis results from increased de novo lipogenesis (DNL). In contrast, ADAPT predicted that the hepatic influx of free fatty acids is the major contributor to hepatic TG accumulation in the early phase of LXR activation. Qualitative validation of this prediction showed a 5-fold increase in the contribution of plasma palmitate to hepatic monounsaturated fatty acids on acute LXR activation, whereas DNL was not yet significantly increased. This study illustrates that complex effects of pharmacological intervention can be translated into distinct patterns of metabolic regulation through state-of-the-art mathematical modeling.
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Brenda S
authors.initials: BS
authors.lastname: Hijmans
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Tiemann
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Boesjes
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Natal A W
authors.initials: NA
authors.lastname: van Riel
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Departments of *Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Netherlands Consortium for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Groningen Centre for Systems Biology, University of Groningen, Groningen, The Netherlands m.h.oosterveer@umcg.nl.
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D003198:Computer Simulation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000633:toxicity; D050155:Lipogenesis; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity; D049490:Systems Biology; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D005230:Fatty Acids, Nonesterified; D006845:Hydrocarbons, Fluorinated; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D013449:Sulfonamides; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C030106:very low density lipoprotein triglyceride
keywords: FFA flux; T0901317; VLDL metabolism; computational modeling; fatty liver