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Oct 4, 2013 (3 years and 10 months ago)

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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

triglyceride

cholesterol ester

VLDL

IDL

LDL

FFA

HDL

chylomicron

remnants

Véniant

et al.

TG

TG

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

FA

FA

ACAT

TG

CE

Apo B

Apo B

FFA

FA

FA

TG / CE /
Glycerol

MTP

DGAT2

FA

FAS

MGK

G
3P

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

FA

FA

ACAT

TG

CE

Apo B

Apo B

FFA

FA

FA

TG / CE /
Glycerol

MTP

DGAT2

FA

FAS

MGK

G
3P

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

FA

FA

ACAT

TG

CE

Apo B

Apo B

FFA

FA

FA

TG / CE /
Glycerol

MTP

DGAT2

FA

FAS

MGK

G
3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

Literature

Quantitative 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

FA

FA

ACAT

TG

CE

Apo B

Apo B

FFA

FA

FA

TG / CE /
Glycerol

MTP

DGAT2

FA

FAS

MGK

G
3P

DGK

MGAT

Liver

Peripheral

Lipoprotein Type Matrix

cholesterol


triglyceride


0


1000


2000

0


5000


10000

Cholesterol: 1000

Triglyceride: 5000

particle uptake

hydrolysis

Different lipoprotein types


Based on triglyceride and cholesterol content


Color represents concentration of lipoprotein type

content
transfer

VLDL production

cholesterol


triglyceride



VLDL production



Particle uptake



Hydrolysis



CETP

9

10



Apo B



TG



CE

cholesterol


triglyceride



VLDL production



Particle uptake



Hydrolysis



CETP

10

9

cholesterol


triglyceride


10

9

1


VLDL production



Particle uptake



Hydrolysis



CETP

cholesterol


triglyceride


10

10

1

9

9

1


VLDL production



Particle uptake



Hydrolysis



CETP

CETP

Acknowledgements

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