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Computational Modeling of Hepatic Lipid and Lipoprotein Metabolism

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  1. Computational Modeling of Hepatic Lipid and Lipoprotein Metabolism NCSB / NBIC Modelers-Bioinformatics Meeting 26-02-2010

  2. Leiden University Medical Center BioModeling & bioInformatics Biomedical NMR Overall aim: Development of mathematical models describing lipid and carbohydrate metabolism at whole body and organ specific level in mice

  3. triglyceride cholesterol ester HDL LDL IDL VLDL chylomicron remnants FFA

  4. Véniantet al.

  5. TG Liang et al. Zhang et al. Boogaerts et al. TG TG TG Grefhorst et al. Davis et al. Dixon et al. TG Millar et al. Wong et al. Horton et al.

  6. Part I Part II FA metabolism Ketogenesis NEFA Lipogenesis apoB metabolism Lipolysis Remnant catabolism

  7. GK Liver Glycerol G3P FA G3P GPAT / AGPAT FA MGL LPA MGK FA GPAT / AGPAT PA MG PPAP2 MGAT HSL:FABP4 DGK FA DAG C FAS FA FA FA FA FA TGH HSL:FABP4 ACAT HSL:FABP4 DGAT1 TG / CE / Glycerol TG CE FA FA Apo B DGAT2 MTP TG CE Apo B Lipoprotein Type Matrix FFA Peripheral

  8. GK Liver Glycerol G3P FA G3P GPAT / AGPAT FA MGL LPA MGK FA GPAT / AGPAT PA MG PPAP2 MGAT HSL:FABP4 DGK FA DAG C FAS FA FA FA FA FA TGH HSL:FABP4 ACAT HSL:FABP4 DGAT1 TG / CE / Glycerol TG CE FA FA Apo B DGAT2 MTP TG CE Apo B Lipoprotein Type Matrix FFA Peripheral

  9. GK Liver Glycerol G3P FA G3P GPAT / AGPAT FA MGL LPA MGK FA GPAT / AGPAT PA MG PPAP2 MGAT HSL:FABP4 DGK FA DAG C FAS FA FA FA FA FA TGH HSL:FABP4 ACAT HSL:FABP4 DGAT1 TG / CE / Glycerol TG CE FA FA Apo B DGAT2 MTP TG CE Apo B Lipoprotein Type Matrix FFA Peripheral

  10. Quantitative data generation Literature • Text mining techniques to infer quantitative information (PHASAR / BioMeta) • Inferring pathway topologies in a more structured way Bijland et al. parameter estimation Exhaustingly searching for kinetic parameters and specie concentrations

  11. GK Liver Glycerol G3P FA G3P GPAT / AGPAT FA MGL LPA MGK FA GPAT / AGPAT PA MG PPAP2 MGAT HSL:FABP4 DGK FA DAG C FAS FA FA FA FA FA TGH HSL:FABP4 ACAT HSL:FABP4 DGAT1 TG / CE / Glycerol TG CE FA FA Apo B DGAT2 MTP TG CE Apo B Lipoprotein Type Matrix FFA Peripheral

  12. Cholesterol: 1000 Triglyceride: 5000 0 5000 10000 triglyceride  VLDL production particle uptake hydrolysis content transfer 0 1000 2000 cholesterol  Different lipoprotein types • Based on triglyceride and cholesterol content • Color represents concentration of lipoprotein type

  13. Apo B • TG • CE 9 10 triglyceride  cholesterol  • VLDL production • Particle uptake • Hydrolysis • CETP

  14. 10 9 triglyceride  cholesterol  • VLDL production • Particle uptake • Hydrolysis • CETP

  15. 10 9 triglyceride  1 cholesterol  • VLDL production • Particle uptake • Hydrolysis • CETP

  16. CETP 1 10 9 10 9 triglyceride  1 cholesterol  • VLDL production • Particle uptake • Hydrolysis • CETP

  17. Peter Hilbers Natal van Riel Jeroen Jeneson Joep Vanlier Joep Schmitz Çeylan Cölmekçi Ko Willems van Dijk Jan Bert van Klinken Sjoerd van den Berg Silvia Bijland Acknowledgements