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BIOMD0000000498 - Mitchell2013 - Liver Iron Metabolism

 

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Reference Publication
Publication ID: 24244122
Mitchell S, Mendes P.
A computational model of liver iron metabolism.
PLoS Comput. Biol. 2013; 9(11): e1003299
School of Computer Science and Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.  [more]
Model
Original Model: BIOMD0000000498.origin
Submitter: Simon Mitchell
Submission ID: MODEL1302260000
Submission Date: 26 Feb 2013 15:05:41 UTC
Last Modification Date: 10 Oct 2014 11:37:44 UTC
Creation Date: 27 Nov 2013 11:28:41 UTC
Encoders:  Vijayalakshmi Chelliah
   Simon Mitchell
set #1
bqbiol:hasProperty Human Disease Ontology hemochromatosis
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:isPartOf Gene Ontology hepatocyte homeostasis
set #4
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Mitchell2013 - Liver Iron Metabolism

The model includes the core regulatory components of human liver iron metabolism.

This model is described in the article:

Mitchell S, Mendes P.
PLoS Comput. Biol. 2013 Nov; 9(11): e1003299

Abstract:

Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.

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: 24244122 Submission Date: 26 Feb 2013 15:05:41 UTC Last Modification Date: 10 Oct 2014 11:37:44 UTC Creation Date: 27 Nov 2013 11:28:41 UTC
Mathematical expressions
Reactions
Fpn Export TfR1 expression TfR1 degradation Ferroportin Expression
IRP expresion IRP degradation Fpn degradation HFE degradation
HFE expression TfR2 expression TfR2 degradation Hepcidin expression
Hepcidin degradation HFE TfR1 binding HFE TfR1 release TfR1 binding
TfR1 release HFE TfR2 binding HFE TfR2 release TfR2 binding
TfR2 release TfR1 binding 2 TfR1 release 2 HFE TfR1 binding 2
HFE TfR1 release 2 TfR2 binding 2 TfR2 release 2 TfR1 iron internalisation
TfR2 iron internalisation outFlow Ferritin Iron binding Ferritin Iron release
Ferritin Iron internalisation Ferritin internalised iron release ferritin expression Ferritin Degredation Full
Ferritin Degredation Full Iron Release HFETfR degradation HFETfR2 degradation Heme uptake
Heme export HO1 exp HO1 Deg Heme oxygenation
Rules
Assignment Rule (variable: Fe2GutQUant)      
Physical entities
Compartments Species
LiverCell Hamp Fe-FT FT
FT1 HO-1 Heme
LIP Fpn IRP
     
intercell Tf-Fe_intercell TfR Tf-Fe-TfR1
HFE HFE-TfR Tf-Fe-TfR2
2(Tf-Fe)-TfR1 2HFE-TfR 2HFE-TfR2
2(Tf-Fe)-TfR2 TfR2 Heme_intercell
Global parameters
Fe2GutQUant      
Reactions (44)
 
 Fpn Export 2.0 × [LIP] → [Tf-Fe_intercell];   {Fpn} , {Fpn} , {LIP} , {Fpn} , {LIP}
 
 TfR1 expression  → [TfR];   {IRP} , {IRP} , {IRP}
 
 TfR1 degradation [TfR] → ;   {TfR} , {TfR}
 
 Ferroportin Expression  → [Fpn];   {IRP} , {IRP} , {IRP}
 
 IRP expresion  → [IRP];   {LIP} , {LIP} , {LIP}
 
 IRP degradation [IRP] → ;   {IRP} , {IRP}
 
 Fpn degradation [Fpn] → ;   {Hamp} , {Hamp} , {Fpn} , {Hamp} , {Fpn}
 
 HFE degradation [HFE] → ;   {HFE} , {HFE}
 
 HFE expression  → [HFE];  
 
 TfR2 expression  → [TfR2];  
 
 TfR2 degradation [TfR2] → ;   {Tf-Fe_intercell} , {Tf-Fe_intercell} , {TfR2} , {Tf-Fe_intercell} , {TfR2}
 
 Hepcidin expression  → [Hamp];   {2HFE-TfR2} , {2(Tf-Fe)-TfR2} , {2HFE-TfR2} , {2(Tf-Fe)-TfR2} , {2HFE-TfR2} , {2(Tf-Fe)-TfR2}
 
 Hepcidin degradation [Hamp] → ;   {Hamp} , {Hamp}
 
 HFE TfR1 binding [HFE] + [TfR] → [HFE-TfR];   {HFE} , {TfR} , {HFE} , {TfR}
 
 HFE TfR1 release [HFE-TfR] → [HFE] + [TfR];   {HFE-TfR} , {HFE-TfR}
 
 TfR1 binding [Tf-Fe_intercell] + [TfR] → [Tf-Fe-TfR1];   {Tf-Fe_intercell} , {TfR} , {Tf-Fe_intercell} , {TfR}
 
 TfR1 release [Tf-Fe-TfR1] → [Tf-Fe_intercell] + [TfR];   {Tf-Fe-TfR1} , {Tf-Fe-TfR1}
 
 HFE TfR2 binding 2.0 × [HFE] + [TfR2] → [2HFE-TfR2];   {HFE} , {TfR2} , {HFE} , {TfR2}
 
 HFE TfR2 release [2HFE-TfR2] → 2.0 × [HFE] + [TfR2];   {2HFE-TfR2} , {2HFE-TfR2}
 
 TfR2 binding [Tf-Fe_intercell] + [TfR2] → [Tf-Fe-TfR2];   {Tf-Fe_intercell} , {TfR2} , {Tf-Fe_intercell} , {TfR2}
 
 TfR2 release [Tf-Fe-TfR2] → [Tf-Fe_intercell] + [TfR2];   {Tf-Fe-TfR2} , {Tf-Fe-TfR2}
 
 TfR1 binding 2 [Tf-Fe-TfR1] + [Tf-Fe_intercell] → [2(Tf-Fe)-TfR1];   {Tf-Fe-TfR1} , {Tf-Fe_intercell} , {Tf-Fe-TfR1} , {Tf-Fe_intercell}
 
 TfR1 release 2 [2(Tf-Fe)-TfR1] → [Tf-Fe-TfR1] + [Tf-Fe_intercell];   {2(Tf-Fe)-TfR1} , {2(Tf-Fe)-TfR1}
 
 HFE TfR1 binding 2 [HFE-TfR] + [HFE] → [2HFE-TfR];   {HFE-TfR} , {HFE} , {HFE-TfR} , {HFE}
 
 HFE TfR1 release 2 [2HFE-TfR] → [HFE-TfR] + [HFE];   {2HFE-TfR} , {2HFE-TfR}
 
 TfR2 binding 2 [Tf-Fe-TfR2] + [Tf-Fe_intercell] → [2(Tf-Fe)-TfR2];   {Tf-Fe-TfR2} , {Tf-Fe_intercell} , {Tf-Fe-TfR2} , {Tf-Fe_intercell}
 
 TfR2 release 2 [2(Tf-Fe)-TfR2] → [Tf-Fe-TfR2] + [Tf-Fe_intercell];   {2(Tf-Fe)-TfR2} , {2(Tf-Fe)-TfR2}
 
 TfR1 iron internalisation [2(Tf-Fe)-TfR1] → 4.0 × [LIP] + [TfR];   {2(Tf-Fe)-TfR1} , {2(Tf-Fe)-TfR1}
 
 TfR2 iron internalisation [2(Tf-Fe)-TfR2] → 4.0 × [LIP] + [TfR2];   {2(Tf-Fe)-TfR2} , {2(Tf-Fe)-TfR2}
 
 outFlow [LIP] → ;   {LIP} , {LIP}
 
 Ferritin Iron binding [LIP] + [FT] → [Fe-FT];   {LIP} , {FT} , {LIP} , {FT}
 
 Ferritin Iron release [Fe-FT] → [LIP] + [FT];   {Fe-FT} , {Fe-FT}
 
 Ferritin Iron internalisation [Fe-FT] → [FT1] + [FT];   {Fe-FT} , {Fe-FT}
 
 Ferritin internalised iron release [FT1] → [LIP];   {FT1} , {FT} , {FT1} , {FT} , {FT1} , {FT}
 
 ferritin expression  → [FT];   {IRP} , {IRP} , {IRP}
 
 Ferritin Degredation Full [FT] → ;   {FT} , {FT}
 
 Ferritin Degredation Full Iron Release [FT1] → [LIP];   {FT1} , {FT} , {FT1} , {FT} , {FT1} , {FT}
 
 HFETfR degradation [2HFE-TfR] → ;   {2HFE-TfR} , {2HFE-TfR}
 
 HFETfR2 degradation [2HFE-TfR2] → ;   {2HFE-TfR2} , {2HFE-TfR2}
 
 Heme uptake [Heme_intercell] → [Heme];   {Heme_intercell} , {Heme_intercell}
 
 Heme export [Heme] → [Heme_intercell];   {Heme} , {Heme}
 
 HO1 exp  → [HO-1];   {Heme} , {Heme} , {Heme}
 
 HO1 Deg [HO-1] → ;   {HO-1} , {HO-1}
 
 Heme oxygenation [Heme] → [LIP];   {HO-1} , {HO-1} , {Heme} , {HO-1} , {Heme}
 
Rules (1)
 
 Assignment Rule (name: parameter_1) Fe2GutQUant = piecewise(1E-7, (((-5E-13)*(time-40000)^2+0.0001) < 1E-7), (-5E-13)*(time-40000)^2+0.0001)
 
Functions (12)
 
 Constant flux (irreversible) lambda(v, v)
 
 Henri-Michaelis-Menten (irreversible) lambda(substrate, Km, V, V*substrate/(Km+substrate))
 
 Hill Function -| lambda(a, M, n, K, a*(1-M^n/(K^n+M^n)))
 
 Hill Function -> lambda(a, n, K, M, a*M^n/(K^n+M^n))
 
 Biochemical Hill Function -> (workaround) lambda(a, M, n, K, L, a*M^n/(K^n+M^n)*L)
 
 Biochemical Hill Function -| (workaround) lambda(a, M, n, K, L, a*(1-M^n/(K^n+M^n))*L)
 
 Hill expression lambda(a, M, K, a*M/(K+M))
 
 Kloss Hill [1] lambda(S, kloss, FT1, FT, S*kloss*(1+0.048*FT1/FT/(1+FT1/FT)))
 
 Mass Action Ferritin [2] lambda(K, FT1, FT, S, K*FT1/FT*S)
 
 Biochemical Hill Function General lambda(a, M, n, K, S, a*M^n/(K^n+M^n)*S)
 
 Henri-Michaelis-Menten kcat (irreversible) [1] lambda(E, C, S, K, E*C*S/(K+S))
 
 Hepc Expression 7 [1] lambda(basal, a, M, n, K, a1, M1, K1, basal+a*M^n/(K^n+M^n)+a1*M1/(K1+M1))
 
 LiverCell Spatial dimensions: 3.0  Compartment size: 1.0
 
 Hamp
Compartment: LiverCell
Initial concentration: 5.0E-9
 
 Fe-FT
Compartment: LiverCell
Initial concentration: 0.0
 
 FT
Compartment: LiverCell
Initial concentration: 1.66E-10
 
 FT1
Compartment: LiverCell
Initial concentration: 0.0
 
 HO-1
Compartment: LiverCell
Initial concentration: 3.56E-11
 
 Heme
Compartment: LiverCell
Initial concentration: 1.0E-9
 
 LIP
Compartment: LiverCell
Initial concentration: 1.3E-6
 
 Fpn
Compartment: LiverCell
Initial concentration: 1.0E-9
 
 IRP
Compartment: LiverCell
Initial concentration: 1.16E-6
 
 intercell Spatial dimensions: 3.0  Compartment size: 1.0
 
 Tf-Fe_intercell
Compartment: intercell
Initial concentration: 5.0E-6
Constant
 
 TfR
Compartment: intercell
Initial concentration: 4.0E-7
 
 Tf-Fe-TfR1
Compartment: intercell
Initial concentration: 0.0
 
 HFE
Compartment: intercell
Initial concentration: 2.0E-7
 
 HFE-TfR
Compartment: intercell
Initial concentration: 0.0
 
 Tf-Fe-TfR2
Compartment: intercell
Initial concentration: 0.0
 
 2(Tf-Fe)-TfR1
Compartment: intercell
Initial concentration: 0.0
 
 2HFE-TfR
Compartment: intercell
Initial concentration: 0.0
 
 2HFE-TfR2
Compartment: intercell
Initial concentration: 0.0
 
 2(Tf-Fe)-TfR2
Compartment: intercell
Initial concentration: 0.0
 
 TfR2
Compartment: intercell
Initial concentration: 3.0E-6
 
 Heme_intercell
Compartment: intercell
Initial concentration: 1.0E-7
Constant
 
Global Parameters (1)
 
  Fe2GutQUant
Value: 1.0E-7
 
Fpn Export (3)
 
   a
Value: 2.0
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 3.0E-6
Constant
 
TfR1 expression (3)
 
   a
Value: 6.0E-12
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 1.0E-6
Constant
 
TfR1 degradation (1)
 
   k1
Value: 8.37E-6
Constant
 
Ferroportin Expression (3)
 
   a
Value: 1.0E-9
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 5.0E-6
Constant
 
IRP expresion (3)
 
   a
Value: 4.0E-11
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 1.0E-6
Constant
 
IRP degradation (1)
 
   k1
Value: 1.597E-5
Constant
 
Fpn degradation (3)
 
   a
Value: 2.315E-4
Constant
 
   n
Value: 5.0
Constant
 
   K
Value: 5.0E-9
Constant
 
HFE degradation (1)
 
   k1
Value: 6.418E-5
Constant
 
HFE expression (1)
 
   v
Value: 2.3469E-11
Constant
 
TfR2 expression (1)
 
   v
Value: 3.0E-11
Constant
 
TfR2 degradation (3)
 
   a
Value: 3.2E-5
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 2.5E-6
Constant
 
Hepcidin expression (6)
 
   basal
Constant
 
   a
Value: 5.0E-12
Constant
 
   n
Value: 5.0
Constant
 
   K
Value: 1.35E-7
Constant
 
   a1
Value: 5.0E-12
Constant
 
   K1
Value: 6.0E-7
Constant
 
Hepcidin degradation (1)
 
   k1
Value: 5.6E-4
Constant
 
HFE TfR1 binding (1)
 
   k1
Value: 1102000.0
Constant
 
HFE TfR1 release (1)
 
   k1
Value: 0.08
Constant
 
TfR1 binding (1)
 
   k1
Value: 837400.0
Constant
 
TfR1 release (1)
 
   k1
Value: 9.142E-4
Constant
 
HFE TfR2 binding (1)
 
   k1
Value: 3.9438E11
Constant
 
HFE TfR2 release (1)
 
   k1
Value: 0.0018
Constant
 
TfR2 binding (1)
 
   k1
Value: 222390.0
Constant
 
TfR2 release (1)
 
   k1
Value: 0.0061
Constant
 
TfR1 binding 2 (1)
 
   k1
Value: 121400.0
Constant
 
TfR1 release 2 (1)
 
   k1
Value: 0.003535
Constant
 
HFE TfR1 binding 2 (1)
 
   k1
Value: 1102000.0
Constant
 
HFE TfR1 release 2 (1)
 
   k1
Value: 0.08
Constant
 
TfR2 binding 2 (1)
 
   k1
Value: 69600.0
Constant
 
TfR2 release 2 (1)
 
   k1
Value: 0.024
Constant
 
TfR1 iron internalisation (1)
 
   k1
Value: 0.8333
Constant
 
TfR2 iron internalisation (1)
 
   k1
Value: 0.8333
Constant
 
outFlow (1)
 
   k1
Value: 4.0E-4
Constant
 
Ferritin Iron binding (1)
 
   k1
Value: 4.71E10
Constant
 
Ferritin Iron release (1)
 
   k1
Value: 22922.0
Constant
 
Ferritin Iron internalisation (1)
 
   k1
Value: 108000.0
Constant
 
Ferritin internalised iron release (1)
 
   kloss
Value: 13.112
Constant
 
ferritin expression (3)
 
   a
Value: 2.312E-13
Constant
 
   n
Value: 1.0
Constant
 
   K
Value: 1.0E-6
Constant
 
Ferritin Degredation Full (1)
 
   k1
Value: 1.203E-5
Constant
 
Ferritin Degredation Full Iron Release (1)
 
   K
Value: 1.203E-5
Constant
 
HFETfR degradation (1)
 
   k1
Value: 8.37E-7
Constant
 
HFETfR2 degradation (1)
 
   k1
Value: 8.37E-5
Constant
 
Heme uptake (2)
 
   Km
Value: 1.25E-4
Constant
 
   V
Value: 1.034E-5
Constant
 
Heme export (2)
 
   Km
Value: 1.78E-5
Constant
 
   V
Value: 2.18E-5
Constant
 
HO1 exp (2)
 
   a
Value: 2.1432E-15
Constant
 
   K
Value: 1.0E-9
Constant
 
HO1 Deg (1)
 
   k1
Value: 3.209E-5
Constant
 
Heme oxygenation (2)
 
   C
Value: 17777.7
Constant
 
   K
Value: 2.0E-6
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000498

Curator's comment: (updated: 27 Nov 2013 11:26:28 GMT)

Figure 3 of the reference publication is reproduced here. There is a typo in the legend in figure3a of the paper. 2HFE-TfR should be HFE-TfR. This has been checked with the author. The Copasi file with the conditions to simulate this plot can be downloaded from the link below.
The model was simulated using Copasi v4.11 (Build 64). The plots were generated using gnuplot.

Additional information: The author has provided additional information to generate other plots in the paper.
1. To recreate Figure 4 of the paper, add another parameter scan for HFE expression between 2.3469e-13 and 2.3469e-11.
2. The setup for Figures 5, 6 and 7 of the paper involves defining a number of global quantities and initial concentrations. [See attached Copasi file below]

Additional file(s)
  • Conditions to do parameter scan:
    Copasi file with conditions to reproduce figure 3 of the paper
  • Copasi file to generate Figures 5, 6 and 7:
    The setup for Figures 5, 6 and 7 involves defining a number of global quantities and initial concentrations. The Copasi file provides the correct tasks set up.
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