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BIOMD0000000434 - McAuley2012 - Whole-body Cholesterol Metabolism

 

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Reference Publication
Publication ID: 23046614
Mc Auley MT, Wilkinson DJ, Jones JJ, Kirkwood TB.
A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation.
BMC Syst Biol 2012; 6: 130
Campus for Ageing and Vitality, Newcastle University, Henry Wellcome Biogerontology Building, Newcastle upon Tyne NE4 5PL, United Kingdom. mcaulem@hope.ac.uk  [more]
Model
Original Model: McAuleyetalWholeBodyCholes...
Submitter: Mark Mc Auley
Submission ID: MODEL1206010000
Submission Date: 01 Jun 2012 12:06:32 UTC
Last Modification Date: 12 Feb 2013 15:37:44 UTC
Creation Date: 27 Nov 2012 16:32:48 UTC
Encoders:  Vijayalakshmi Chelliah
   Mark Mc Auley
set #1
bqbiol:isVersionOf Gene Ontology age-dependent general metabolic decline
Gene Ontology cholesterol metabolic process
set #2
bqbiol:isVersionOf Taxonomy Homo sapiens
Notes
McAuley2012 - Whole-body Cholesterol Metabolism

Lipid metabolism has a key role to play in human longevity and healthy aging. A whole-body mathematical model of cholesterol metabolism that explores the changes in both the rate of intestinal cholesterol absorption and the hepatic rate of clearance of LDL-C from the plasma, has been presented here. The model showed that of these two mechanisms, changes to the rate of LDL-C removal from the plasma with age had the most significant effect on cholesterol metabolism.

The original SBML model file was generated using MathSBML 2.5.1.

This model is described in the article:

Mc Auley MM, Wilkinson DJ, Jones JJ, Kirkwood TT.
BMC Syst Biol. 2012 Oct 10;6(1):130.

Abstract:

BACKGROUND: Global demographic changes have stimulated marked interest in the process of ageing. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD) has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C) has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion.

RESULTS: The model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116mg/dL.

CONCLUSIONS: Our model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 23046614 Submission Date: 01 Jun 2012 12:06:32 UTC Last Modification Date: 12 Feb 2013 15:37:44 UTC Creation Date: 27 Nov 2012 16:32:48 UTC
Mathematical expressions
Reactions
Ingestion Intestinal Cholesterol Synthesis Bile Salt Release Bile Salt Return
Bile Salt Excretion Bile Salt Synthesis Cholesterol Absorption Cholesterol Excretion
Intestinal Nascent HDL Synthesis Billary Cholesterol Release Hepatic Cholesterol Synthesis Hepatic Cholesterol Storage
Release of Stored Cholesterol Hepatic Nascent HDL Synthesis VLDL Cholesterol Formation Hepatic LDLR Synthesis
Hepatic LDL Receptor Degradation VLDL Cholesterol ReUptake IDL Cholesterol Formation IDL Cholesterol ReUptake
LDL Cholesterol Formation Receptor Dependent Hepatic Uptake Receptor Independent Hepatic Uptake Receptor Dependent Peripheral Uptake
Receptor Independent Peripheral Uptake Peripheral LDLR Synthesis Peripheral LDL Receptor Degradation Peripheral Cholesterol Storage
Release of Stored Peripheral Cholesterol Peripheral Steroid Production HDL Cholesterol Formation Peripheral Cholesterol Synthesis
CETP Mediated Transfer To VLDL CETP Mediated TransferTo LDL Reverse Cholesterol Transport  
Physical entities
Compartments Species
Intake DC    
Intestine IC ICS IBS
     
HepaticTissue HBS HFC HCS
HCE ACAT CEH
HNHDLS HLDLRs HLDLRsS
HLDLRD SRB1  
PeripheralTissue PFC PLDLRs PLDLRsS
PLDLRD PCE PSS
PCS    
Plasma INHDLS NHDL VLDLC
IDLC LPL LDLC
HSL HDLC LCAT
CETP    
Excreted EBS EC  
Reactions (35)
 
 Ingestion [DC] → [IC];   {DC}
 
 Intestinal Cholesterol Synthesis [ICS] → [IC];   {IC} , {IC}
 
 Bile Salt Release [HBS] → [IBS];   {HBS}
 
 Bile Salt Return [IBS] → [HBS];   {IBS}
 
 Bile Salt Excretion [IBS] → [EBS];   {IBS}
 
 Bile Salt Synthesis [HFC] → [HBS];   {HBS} , {HFC} , {HBS}
 
 Cholesterol Absorption [IC] → [HFC];   {IBS} , {IC} , {IBS}
 
 Cholesterol Excretion [IC] → [EC];   {IBS} , {IC} , {IBS}
 
 Intestinal Nascent HDL Synthesis [INHDLS] → [NHDL];   {PFC} , {PFC}
 
 Billary Cholesterol Release [HFC] → [IC];   {HFC} , {HFC}
 
 Hepatic Cholesterol Synthesis [HCS] → [HFC];   {HFC} , {HFC}
 
 Hepatic Cholesterol Storage [HFC] → [HCE];   {ACAT} , {HFC} , {ACAT} , {HFC}
 
 Release of Stored Cholesterol [HCE] → [HFC];   {CEH} , {HCE} , {CEH} , {HCE}
 
 Hepatic Nascent HDL Synthesis [HNHDLS] → [NHDL];   {PFC} , {PFC}
 
 VLDL Cholesterol Formation [HFC] → [VLDLC];   {HFC}
 
 Hepatic LDLR Synthesis [HLDLRsS] → [HLDLRs];   {HLDLRsS} , {HFC} , {HLDLRsS} , {HFC}
 
 Hepatic LDL Receptor Degradation [HLDLRs] → [HLDLRD];   {HLDLRs}
 
 VLDL Cholesterol ReUptake [VLDLC] → [HFC];   {VLDLC}
 
 IDL Cholesterol Formation [VLDLC] → [IDLC];   {VLDLC} , {LPL} , {VLDLC} , {LPL}
 
 IDL Cholesterol ReUptake [IDLC] → [HFC];   {IDLC}
 
 LDL Cholesterol Formation [IDLC] → [LDLC];   {HSL} , {IDLC} , {HSL}
 
 Receptor Dependent Hepatic Uptake [LDLC] → [HFC];   {HLDLRs} , {LDLC} , {HLDLRs}
 
 Receptor Independent Hepatic Uptake [LDLC] → [HFC];   {LDLC}
 
 Receptor Dependent Peripheral Uptake [LDLC] → [PFC];   {PLDLRs} , {PLDLRs} , {LDLC}
 
 Receptor Independent Peripheral Uptake [LDLC] → [PFC];   {LDLC}
 
 Peripheral LDLR Synthesis [PLDLRsS] → [PLDLRs];   {PFC} , {PLDLRsS} , {PFC}
 
 Peripheral LDL Receptor Degradation [PLDLRs] → [PLDLRD];   {PLDLRs}
 
 Peripheral Cholesterol Storage [PFC] → [PCE];   {ACAT} , {ACAT} , {PFC}
 
 Release of Stored Peripheral Cholesterol [PCE] → [PFC];   {CEH} , {CEH} , {PCE}
 
 Peripheral Steroid Production [PFC] → [PSS];   {PFC}
 
 HDL Cholesterol Formation [PFC] + [NHDL] → [HDLC];   {LCAT} , {PFC} , {NHDL} , {LCAT}
 
 Peripheral Cholesterol Synthesis [PCS] → [PFC];   {PFC}
 
 CETP Mediated Transfer To VLDL [HDLC] → [VLDLC];   {CETP} , {HDLC} , {CETP}
 
 CETP Mediated TransferTo LDL [HDLC] → [LDLC];   {CETP} , {HDLC} , {CETP}
 
 Reverse Cholesterol Transport [HDLC] → [HFC];   {SRB1} , {HDLC} , {SRB1}
 
Functions (23)
 
 Rate Law for Intestinal Cholesterol Synthesis lambda(ICSmax, IC, ICt, IS, ICSmax/(1+(IC/ICt)^IS))
 
 Rate Law for Bile Salt Synthesis lambda(k5, HFC, HBS, k5*HFC/HBS)
 
 Rate Law for Cholesterol Absorption lambda(k6, IC, IBS, k6*IC*IBS)
 
 Rate Law for Cholesterol Excretion lambda(k7, IC, IBS, k7*IC*IBS)
 
 Rate Law for Intestinal Nascent HDL Synthesis lambda(k8, PFC, k8*PFC)
 
 Rate Law for Billary Cholesterol Release lambda(BCRmax, BCRt, HFC, BS, BCRmax/(1+(BCRt/HFC)^BS))
 
 Rate Law for Hepatic Cholesterol Synthesis lambda(HCSmax, HFC, HCSt, HS, HCSmax/(1+(HFC/HCSt)^HS))
 
 Rate Law for Hepatic Cholesterol Storage_1 lambda(k9, ACAT, HFC, k9*ACAT*HFC)
 
 Rate Law for Release of Stored Cholesterol lambda(k10, CEH, HCE, k10*CEH*HCE)
 
 Rate Law for Hepatic Nascent HDL Synthesis lambda(k11, PFC, k11*PFC)
 
 Rate Law for Hepatic LDLR Synthesis lambda(khrs, HLDLRsS, HFC, khrs*HLDLRsS/HFC)
 
 Rate Law for IDL Cholesterol Formation lambda(k15, VLDLC, LPL, k15*VLDLC*LPL)
 
 Rate Law for LDL Cholesterol Formation lambda(k17, IDLC, HSL, k17*IDLC*HSL)
 
 Rate Law for Receptor Dependent Hepatic Uptake lambda(k18, LDLC, HLDLRs, k18*LDLC*HLDLRs)
 
 Rate Law for Receptor Dependent Peripheral Uptake lambda(k20, PLDLRs, LDLC, k20*PLDLRs*LDLC)
 
 Rate Law for Peripheral LDLR Synthesis lambda(kprs, PLDLRsS, PFC, kprs*PLDLRsS/PFC)
 
 Rate Law for Peripheral Cholesterol Storage lambda(k23, ACAT, PFC, k23*ACAT*PFC)
 
 Rate Law for Release of Stored Peripheral Cholesterol lambda(k24, CEH, PCE, k24*CEH*PCE)
 
 Rate Law for HDL Cholesterol Formation lambda(k26, PFC, NHDL, LCAT, k26*PFC*NHDL*LCAT)
 
 Rate Law for Peripheral Cholesterol Synthesis lambda(PCSmax, PFC, PPCt, PCSS, PCSmax/(1+(PFC/PPCt)^PCSS))
 
 Rate Law for CETP Mediated Transfer To VLDL lambda(k27, HDLC, CETP, k27*HDLC*CETP)
 
 Rate Law for CETP Mediated TransferTo LDL lambda(k28, HDLC, CETP, k28*HDLC*CETP)
 
 Rate Law for Reverse Cholesterol Transport lambda(k29, HDLC, SRB1, k29*HDLC*SRB1)
 
   Intake Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 DC
Compartment: Intake
Initial concentration: 304.0
Constant
 
 Intestine Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 IC
Compartment: Intestine
Initial concentration: 3150.0
 
 ICS
Compartment: Intestine
Initial concentration: 0.0
Constant
 
 IBS
Compartment: Intestine
Initial concentration: 467.0
 
 HepaticTissue Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 HBS
Compartment: HepaticTissue
Initial concentration: 400.0
 
 HFC
Compartment: HepaticTissue
Initial concentration: 60000.0
 
 HCS
Compartment: HepaticTissue
Initial concentration: 0.0
Constant
 
 HCE
Compartment: HepaticTissue
Initial concentration: 10000.0
 
 ACAT
Compartment: HepaticTissue
Initial concentration: 100.0
 
 CEH
Compartment: HepaticTissue
Initial concentration: 100.0
 
 HNHDLS
Compartment: HepaticTissue
Initial concentration: 0.0
Constant
 
 HLDLRs
Compartment: HepaticTissue
Initial concentration: 100.0
 
 HLDLRsS
Compartment: HepaticTissue
Initial concentration: 600.0
Constant
 
 HLDLRD
Compartment: HepaticTissue
Initial concentration: 0.0
 
 SRB1
Compartment: HepaticTissue
Initial concentration: 100.0
 
 PeripheralTissue Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 PFC
Compartment: PeripheralTissue
Initial concentration: 57516.0
 
 PLDLRs
Compartment: PeripheralTissue
Initial concentration: 100.0
 
 PLDLRsS
Compartment: PeripheralTissue
Initial concentration: 575.16
Constant
 
 PLDLRD
Compartment: PeripheralTissue
Initial concentration: 0.0
 
 PCE
Compartment: PeripheralTissue
Initial concentration: 9363.0
 
 PSS
Compartment: PeripheralTissue
Initial concentration: 0.0
 
 PCS
Compartment: PeripheralTissue
Initial concentration: 0.0
Constant
 
 Plasma Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 INHDLS
Compartment: Plasma
Initial concentration: 0.0
Constant
 
 NHDL
Compartment: Plasma
Initial concentration: 100.0
 
 VLDLC
Compartment: Plasma
Initial concentration: 20.0
 
 IDLC
Compartment: Plasma
Initial concentration: 20.0
 
 LPL
Compartment: Plasma
Initial concentration: 100.0
 
 LDLC
Compartment: Plasma
Initial concentration: 100.0
 
 HSL
Compartment: Plasma
Initial concentration: 100.0
 
 HDLC
Compartment: Plasma
Initial concentration: 45.0
 
 LCAT
Compartment: Plasma
Initial concentration: 100.0
 
 CETP
Compartment: Plasma
Initial concentration: 100.0
 
   Excreted Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 EBS
Compartment: Excreted
Initial concentration: 0.0
 
 EC
Compartment: Excreted
Initial concentration: 0.0
 
Ingestion (1)
 
   k1
Value: 1.0
Constant
 
Intestinal Cholesterol Synthesis (3)
 
   ICSmax
Value: 100.0
Constant
 
   ICt
Value: 3120.0
Constant
 
   IS
Value: 5.0
Constant
 
Bile Salt Release (1)
 
   k1
Value: 6.0
Constant
 
Bile Salt Return (1)
 
   k1
Value: 4.29
Constant
 
Bile Salt Excretion (1)
 
   k1
Value: 0.856
Constant
 
Bile Salt Synthesis (1)
 
   k5
Value: 2.66
Constant
 
Cholesterol Absorption (1)
 
   k6
Value: 5.286E-4
Constant
 
Cholesterol Excretion (1)
 
   k7
Value: 5.286E-4
Constant
 
Intestinal Nascent HDL Synthesis (1)
 
   k8
Value: 5.0E-4
Constant
 
Billary Cholesterol Release (3)
 
   BCRmax
Value: 2000.0
Constant
 
   BCRt
Value: 55326.0
Constant
 
   BS
Value: 5.0
Constant
 
Hepatic Cholesterol Synthesis (3)
 
   HCSmax
Value: 500.0
Constant
 
   HCSt
Value: 93925.0
Constant
 
   HS
Value: 5.0
Constant
 
Hepatic Cholesterol Storage (1)
 
   k9
Value: 1.0
Constant
 
Release of Stored Cholesterol (1)
 
   k10
Value: 5.998
Constant
 
Hepatic Nascent HDL Synthesis (1)
 
   k11
Value: 0.0050
Constant
 
VLDL Cholesterol Formation (1)
 
   k1
Value: 0.016
Constant
 
Hepatic LDLR Synthesis (1)
 
   khrs
Value: 100.0
Constant
 
Hepatic LDL Receptor Degradation (1)
 
   k1
Value: 0.01
Constant
 
VLDL Cholesterol ReUptake (1)
 
   k1
Value: 0.0496
Constant
 
IDL Cholesterol Formation (1)
 
   k15
Value: 0.43
Constant
 
IDL Cholesterol ReUptake (1)
 
   k1
Value: 0.054
Constant
 
LDL Cholesterol Formation (1)
 
   k17
Value: 0.38
Constant
 
Receptor Dependent Hepatic Uptake (1)
 
   k18
Value: 0.068
Constant
 
Receptor Independent Hepatic Uptake (1)
 
   k1
Value: 0.0050
Constant
 
Receptor Dependent Peripheral Uptake (1)
 
   k20
Value: 0.00675
Constant
 
Receptor Independent Peripheral Uptake (1)
 
   k1
Value: 5.0E-6
Constant
 
Peripheral LDLR Synthesis (1)
 
   kprs
Value: 100.0
Constant
 
Peripheral LDL Receptor Degradation (1)
 
   k1
Value: 0.01
Constant
 
Peripheral Cholesterol Storage (1)
 
   k23
Value: 0.017386
Constant
 
Release of Stored Peripheral Cholesterol (1)
 
   k24
Value: 0.1068
Constant
 
Peripheral Steroid Production (1)
 
   k1
Value: 5.0E-4
Constant
 
HDL Cholesterol Formation (1)
 
   k26
Value: 1.5E-5
Constant
 
Peripheral Cholesterol Synthesis (3)
 
   PCSmax
Value: 500.0
Constant
 
   PPCt
Value: 80342.0
Constant
 
   PCSS
Value: 5.0
Constant
 
CETP Mediated Transfer To VLDL (1)
 
   k27
Value: 0.01
Constant
 
CETP Mediated TransferTo LDL (1)
 
   k28
Value: 0.0010
Constant
 
Reverse Cholesterol Transport (1)
 
   k29
Value: 0.05
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000434

Curator's comment: (updated: 27 Nov 2012 16:32:33 GMT)

Figure 1b of the reference publication has been reproduced here. The figure in the paper has been generated using MathSBML. The author has generated the SBML file using Copasi, and finds that with the same intial conditions and parameter sets, LDLC enters a slightly higher steady statem, when running the simulation using Copasi. This is reflected in this curation figure, generated using SBML odeSolver.
The model was simulated using SBML odeSolver and the plot was generated using Gnuplot.

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