A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation
| العنوان: | A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation |
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| المؤلفون: | Folkert Kuipers, Natal A. W. van Riel, Aldo Grefhorst, Maaike H. Oosterveer, Marije Boesjes, Albert K. Groen, Uwe J. F. Tietge, Brenda S. Hijmans, Theo H. van Dijk, CA Christian Tiemann |
| المساهمون: | Computational Biology, Academic Medical Center, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Internal Medicine |
| المصدر: | The FASEB Journal, 29(4), 1153-1164. FASEB FASEB journal, 29(4), 1153-1164. FASEB The FASEB Journal, 29(4), 1153-1164. FEDERATION AMER SOC EXP BIOL FASEB Journal, 29(4), 1153-1164. FASEB |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, computational modeling, Hydrocarbons, Fluorinated, Peroxisome proliferator-activated receptor, Fatty Acids, Nonesterified, Lipoproteins, VLDL, Biochemistry, chemistry.chemical_compound, Phospholipid transfer protein, Liver X Receptors, Mice, Knockout, chemistry.chemical_classification, Sulfonamides, FFA flux, Systems Biology, Fatty liver, PLASMA-CHOLESTEROL, Orphan Nuclear Receptors, Liver, Lipogenesis, PHOSPHOLIPID TRANSFER PROTEIN, FATTY-ACIDS, PPAR-GAMMA, Signal transduction, LIPID-ACCUMULATION, Biotechnology, medicine.medical_specialty, Mice, Transgenic, Biology, Models, Biological, VLDL metabolism, SIGNALING PATHWAYS, LIPOGENESIS, Internal medicine, Genetics, medicine, Animals, Computer Simulation, Liver X receptor, Molecular Biology, Triglycerides, fatty liver, LXR-ALPHA, Triglyceride, Atherosclerosis, medicine.disease, PARTICLE-SIZE, Mice, Inbred C57BL, PPAR gamma, MICE, Endocrinology, chemistry, T0901317, Steatosis |
| الوصف: | 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.—Hijmans, B. S., Tiemann, C. A., Grefhorst, A., Boesjes, M., van Dijk, T. H., Tietge, U. J. F., Kuipers, F., van Riel, N. A. W., Groen, A. K., and Oosterveer, M. H. A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0892-6638 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::619b7344371c44f539e54d7cb658815c https://research.tue.nl/nl/publications/76f8ecc9-25f8-4147-a485-f334ae2b9b71 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....619b7344371c44f539e54d7cb658815c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 08926638 |
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