computational modeling of hepatic lipid and lipoprotein metabolism ncsb / nbic...
TRANSCRIPT
Computational Modeling of Hepatic Lipid and Lipoprotein Metabolism
NCSB / NBIC Modelers-Bioinformatics Meeting
26-02-2010
Overall aim:
Development of mathematical models describing lipid and carbohydrate metabolism at whole body and organ specific level in mice
Leiden University Medical Center BioModeling & bioInformatics Biomedical NMR
triglyceridecholesterol ester
VLDL
IDLLDL
FFA
HDL
chylomicronremnants
Véniant et al.
TGTG
Liang et al.Zhang et al.Boogaerts et al.
TG
TG
Grefhorst et al.Davis et al.Dixon et al.
TG
Millar et al.Wong et al.Horton et al.
FA metabolism
Lipogenesis
Lipolysis
Ketogenesis
apoB metabolism
Remnant catabolism
NEFA
Part I Part II
GPAT / AGPAT
G3P
LPA
PA
DAG
FA
Glycerol
DGAT1
TG
PPAP2
FA
FA FA
GPAT / AGPAT
MG
TGH
HSL:FABP4
HSL:FABP4
FA
MGL
FA
GK
HSL:FABP4
C
CE
FAFA
ACAT
TG CE
Apo B
Apo B
FFA
FAFA
TG / CE / Glycerol
MTP
DGAT2
FAFAS
MGK
G3P
DGK
MGAT
Liver
Peripheral
Lipoprotein Type Matrix
GPAT / AGPAT
G3P
LPA
PA
DAG
FA
Glycerol
DGAT1
TG
PPAP2
FA
FA FA
GPAT / AGPAT
MG
TGH
HSL:FABP4
HSL:FABP4
FA
MGL
FA
GK
HSL:FABP4
C
CE
FAFA
ACAT
TG CE
Apo B
Apo B
FFA
FAFA
TG / CE / Glycerol
MTP
DGAT2
FAFAS
MGK
G3P
DGK
MGAT
Liver
Peripheral
Lipoprotein Type Matrix
, , , ,
, , , , , , , ,
[ ][ ] [ ] [ ] [ ][ ]
[ ][ ] [ ] [ ] [ ]DAG MG MG GLC MG LPA MG DAG
m DAG MG m MG GLC m MG LPA m MG DAG
V MG FA V MG V MG V MGd MG
dt K MG FA K MG K MG K MG
, , ,
, , , , , ,
[ ] [ ][ ] [ ][ ]
[ ] [ ][ ] [ ]C C CE CE C
Cm C m C CE m CE C
V C V C FA V CEd CV
dt K C K C FA K CE
GPAT / AGPAT
G3P
LPA
PA
DAG
FA
Glycerol
DGAT1
TG
PPAP2
FA
FA FA
GPAT / AGPAT
MG
TGH
HSL:FABP4
HSL:FABP4
FA
MGL
FA
GK
HSL:FABP4
C
CE
FAFA
ACAT
TG CE
Apo B
Apo B
FFA
FAFA
TG / CE / Glycerol
MTP
DGAT2
FAFAS
MGK
G3P
DGK
MGAT
Liver
Peripheral
Lipoprotein Type Matrix
, , , ,
, , , , , , , ,
[ ][ ] [ ] [ ] [ ][ ]
[ ][ ] [ ] [ ] [ ]DAG MG MG GLC MG LPA MG DAG
m DAG MG m MG GLC m MG LPA m MG DAG
V MG FA V MG V MG V MGd MG
dt K MG FA K MG K MG K MG
, , ,
, , , , , ,
[ ] [ ][ ] [ ][ ]
[ ] [ ][ ] [ ]C C CE CE C
Cm C m C CE m CE C
V C V C FA V CEd CV
dt K C K C FA K CE
LiteratureQuantitative data generation
Bijland et al.
Exhaustingly searching for
kinetic parameters and specie
concentrations
parameter estimation
• Text mining techniques to infer quantitative information (PHASAR / BioMeta)
• Inferring pathway topologies in a more structured way
GPAT / AGPAT
G3P
LPA
PA
DAG
FA
Glycerol
DGAT1
TG
PPAP2
FA
FA FA
GPAT / AGPAT
MG
TGH
HSL:FABP4
HSL:FABP4
FA
MGL
FA
GK
HSL:FABP4
C
CE
FAFA
ACAT
TG CE
Apo B
Apo B
FFA
FAFA
TG / CE / Glycerol
MTP
DGAT2
FAFAS
MGK
G3P
DGK
MGAT
Liver
Peripheral
Lipoprotein Type Matrix
cholesterol
trig
lyce
ride
0 1000 2000
0
500
0
100
00
Cholesterol: 1000Triglyceride: 5000
particle uptake
hydrolysis
Different lipoprotein types− Based on triglyceride and cholesterol content− Color represents concentration of lipoprotein type
content transfer
VLDL production
cholesterol
trig
lyce
ride
• VLDL production
• Particle uptake
• Hydrolysis
• CETP
910
• Apo B
• TG• CE
cholesterol
trig
lyce
ride
• VLDL production
• Particle uptake
• Hydrolysis
• CETP
109
cholesterol
trig
lyce
ride
109
1
• VLDL production
• Particle uptake
• Hydrolysis
• CETP
cholesterol
trig
lyce
ride
10 10
1
9 9
1
• VLDL production
• Particle uptake
• Hydrolysis
• CETP
CETP
Acknowledgements
Peter Hilbers Natal van Riel Jeroen Jeneson Joep VanlierJoep SchmitzÇeylan Cölmekçi
Ko Willems van DijkJan Bert van Klinken Sjoerd van den Berg Silvia Bijland