The 16th International Scientific Conference

eLearning and Software for Education

Bucharest, April 23-24, 2020
10.12753/2066-026X-20-000

AN E-LEARNING TOOL FOR MATHEMATICAL MODEL OF CHOLESTEROL

HOMEOSTASIS DEPENDING ON DIET AND AGES

Mihai ILEA, Marius TURNEA, Calin CORCIOVA, Mariana ROTARIU

University of Medicine and Pharmacy “Grigore T. Popa”, Str. Universitatii 16, Iasi, Romania
ileamihai2004@yahoo.com, marius.turnea@gmail.com, corciova_calin@yahoo.com, rotariu29@yahoo.com

Abstract: The human health has many important aspects and the cholesterol regulation is one of them.
The low-density lipoproteins cholesterol (LDL-C) transports plasma cholesterol (about 60%) and it is
responsible by its depositing on arteries for atherosclerotic process, increasing the probability of
cardiovascular events. High-density lipoproteins (HDL) can reduce this process by transport about
30% of plasma cholesterol. The balance is modified in the process of aging and depend also of other
factors as diet, and physical exercises. An educational tool is proposing that use basically two
mathematical models: (1) a simple one by two compartment model proposed by Wona & Hrydziuszko
that include an dietary term, and (2) a more complex one that include the mechanism of simulation of
aging proposed by Mc Auley. The values of parameters for both models are taken from literature and
the user can modify them in order to test and simulated the models. The diet is modeled in the first
model as an additive variable, and other variable are deduced from stability analysis and are assumed
based on heuristic trials. In the second model, the mechanism of aging is simulated empirically
(because the complete mechanism is not known yet) by increasing the LDL-C values and decreasing the
number of hepatic LDL receptors (HLDLR) by decreasing the parameter that represents rate of
synthesis. The tool has a library with selected curves for (HDL-C) and (LDL-C) from different
countries of the world by age and sex extracted from literature. In the future development, this
information will be used to model and analytic additive function for (LDL-C) curve by fitting of
parameters with experimental one in system of differential equations that models the cholesterol
homeostasis.

Keywords: cholesterol regulation; mathematical models; simulated, e-learning tools; differential

equations

I. INTRODUCTION

Homeostasis is a general tendency of equilibrium among interdependent elements in living

systems despite of changing conditions [1]. The process of regulation of cholesterol homeostasis has
been known an extensively study during the last decades. The cardiovascular health is connected with
dysregulation of cholesterol metabolism, and as sequel the LDL-C (low density lipoprotein
cholesterol) and HDL-C (high density lipoprotein cholesterol) are considered one of the classic
biomarkers for cardiovascular disease risk.
The models of cholesterol homeostasis will help students to be more familiar with the
components and mechanism that are the support of cholesterol circulatory transport and the influence
of aging on this system.
The early simple model has been propose in [2], based on general two-pool model. The model
is extremely simple and it doesn’t capture the physiological model behind the cholesterol metabolism.
A much more elaborated bi-compartmental model was proposed in [3]. The system is composed from
two simultaneous differential equations (ODEs) cholesterol transported (tissues and muscles) and
dietary cholesterol as separate terms ([3]-[4]). An extension of this model is proposed in [5], where the
cholesterol transported and dietary cholesterol has quadratic sinus forms. The steady state conditions
are calculated using the integrals for quadratic forms of inputs and output mases [5].
From most known eleven models, ten are tested in [6] in order to verify the correct predictions
in line with current knowledge on cholesterol metabolism. Three of them are proved to be correct
predictors of LDL cholesterol (good cholesterol) after treatment with statins [6] as part of functional
test. Meanwhile, the models presented in [6] are practical a review of models used in choesterols
metabolism. A complicated nodel of integrated cholesterol biosynthesis is proposed in [7]. The
SREBP-2 regulation by cholesterol, VLDL (very low density lipoproteins) and LDL uptake along with
receptor biosynthesis are presented in this model [7]. The constructed model is based on initially18
coupled linear and non-linear ODEs, that are reduced uising conservation laws and quasi-steady state
approximations to 12 ODEs [7].
It is known that LDL-C rises significant with age; an average value of 50% by age 65 years is
a common fact [8]. The whole-body systems based model based on cholesterol balance can help the
whole-body cholesterol metabolism and its dysregulation due to aging [8]. A more sophisticated
system which includes an additional 96 mechanisms that are fundamental to cholesterol metabolism
was included in [9]. The result is big system that include144 species and additional 4 species used as
counters for the event reactions.
A recent model has been proposed in [10]. The model includes pharmacokinetic, anti-PCSK9
pharmacodynamics, and statin, and all are used in an integrated network to estimate LDL-C decreasing
after the drug administration [10]. The model can improve the decision making in quantitative systems
pharmacology [10].
A less few mentioned fact is that the LDL-C and HDL-C can have different quantitative
evolution (sometime very significant) in different countries of the world depending on age and sex
[11]. There is no systematically mathematic approach in this direction so we have been chosen to have
a further module that can determine the parameters of the model from experimental data.

II. MODELS OF CHOLESTEROL METABOLISM AND DISSREGULATION

DUE TO AGING

The first model in a bi-compartmental one as it has been proposed in ([3]-[5]). We are not
focused on treatment (with statin as in [7]) but more to pedagogical support to improve the knowledge
about the cholesterol metabolism and the effect on it due to aging.

Figure no. 1. The two-compartment model of cholesterol transport (in lipoproteins). C 1 is the
liver compartment (mass m1, volume V1) and C2 is the blood compartment (mass m2, volume V2). In
this stage of software tool development, k0 = 1.0, ki=1.0, kt=1.0 and kd = 1.0.

The first model implemented in the e-learning tool is that it has been described in ([3]-[4]).
The lipoprotein exogenous pathway includes transport of fat (TAGs) and cholesterol from diet and
also, the reabsorption of recycled cholesterol (via intestine), figure 1. The complex mechanism is
constructed from literature in [3], and the simplified compartment model developed by [3] is used in
pedagogical tool. The system of two ODEs is:

dm1 k11
  k21m2  k12m1  min  mout
dt m1
(1)
dm2
  k21m2  k12m1  mdiet  mtis
dt

The model has a loop in m1 compartment due to apolipoprotein APOA1, included in formulas
as k11/m1. The other quantitities are denoted by: mdiet – dietary cholesterol input, mtis - cholesterol
transport (muscles and peripheral tissue), min - cholesterol from the intestine to the liver and mout -
cholesterol, precursor of bile acids (~8% from bile).
The total of V1+V2 = 55 dl, value taken from literature. The typical values of parameters and
initial values are taken from literature (and collected in [4]): m1= 2,400 mg; m2 = 8,600 mg; V1= 12 dl;
V2 = 43 dl; k11 = 1,500 mg2/min; k12 = 3.58 min-1; k21 = 1.0 min-1; mdiet = 01.1 mg/min; mtis = 0.234
mg/min; min = 1 mg/min; mout = 1.4 mg/min.
The solution of the model is made by numeric methods using the solver ode45() from Matlab.
If the user modify the parameters and a module implemented in software tool detect thta it is the case
of stiff equation, the solver is automatically changed (with no user intervention) in ode12s(), solver for
stiff ODEs. The results are displayed in terms of concentration that is m/V, where m is the mass and V
the volume.
The second model is a network model, proposed by [8]. The model is a balance managed by
coordinate interactions among cholesterol absorption, excretion and synthesis. Let’s denote by X 1 -
Hepatic Bile Salt pool, X2 - Intestinal Bile Salts, X3 - Intestinal Cholesterol, X4 - Excreted Cholesterol,
X5 - Hepatic Free Cholesterol, X6 - Hepatic Cholesterol Esters, X7 - Hepatic Low Density Lipoprotein
Receptors, X8 - Very Low Density Lipoprotein Cholesterol, X 9 - Intermediate Density Lipoprotein
Cholesterol, X10 - Low Density Lipoprotein Cholesterol, X 11 - Peripheral Cholesterol Esters, X 12 -
Peripheral Free Cholesterol, X13 - Nascent High Density Lipoprotein, and X 14 - High Density
Lipoprotein Cholesterol. There are 14 ODEs, and 29 parameters k i, i=1,...,29 [8]. The initial values are
taken from literature and the detailed scenations for simulation are provided using [8] and references
as user manual for biomedical engineers. The system of ODEs is according to [8]:

d[ X1] [X ]
 k5  5  k3  [ X 2 ][ X 3 ]  k2  [ X 1 ]. (2)
dt [ X1]
d[ X 2 ]
 k2  [ X 1 ]  k3  [ X 2 ][ X 3 ]  k4 [ X 2 ]. (3)
dt
d[ X 3 ] 2  10 3
 k1  DC   (k6  k7 )  [ X 2 ][ X 3 ] 
dt 1  (5.55  10 4 /[X 5 ])5
(4)
1  10 2
.
1  ([ X 3 ] / 3.120  10 2 )5

d[ X 4 ]
 k7  [ X 2 ][ X 3 ]. (5)
dt
 d[ X 5 ] 2  103 5  10 2
 k10  100  [ X 6 ]  
dt 1  (5.55  104 /[ X 5 ])5 1  ([ X 5 ] / 9.39  10 4 )5
 k6  [ X 2 ][ X 3 ]  k16  [ X 7 ][ X 9 ]  k18  [ X 7 ][ X 10 ]  k12[ X 5 ]  (6)
[X5]
k29  45  100  k14  [ X 7 ][ X 9 ]  k5   k9 100  [ X 5 ]  k19
[ X1]

d[ X 6 ]
 k9  khr  [ X 5 ]  k10  100  [ X 6 ] (7)
dt
d[ X 7 ] [X ]
 100  7  k13[ X 7 ]
dt [X5]
(8)

d[ X 8 ] (9)
 k12[ X 5 ]  k14  [ X 7 ][ X 8 ]  k15 100  [ X 8 ].
dt

d[ X 9 ]
 k15  100  [ X 8 ]  k16  100  [ X 9 ]  k17  100  [ X 9 ] (10)
dt

d [ X 10 ]
 k17  100  [ X 8 ]  k18 100  [ X 10 ]  k19  [ X 10 ] 
dt (11)
k20 100  [ X 10 ]  k21 

d [ X 11 ] (12)
 k23  100  [ X 12 ]  k24  100  [ X 11 ].
dt

d [ X 12 ] 5  10 2
 k21  k25  k24 100  [ X 11 ]  k23  100  [ X 12 ] 
dt 1  ([ X 12 ] / 5.75  10 4 )5
k20  100  [ X 10 ].
(13)

d [ X 13 ] (14)
 k8  k11
dt
d [ X 14 ]
 k26  100  100  [ X 12 ]  (k27  k28 )  100  [ X 14 ] 
dt (15)
k29  100  [ X 14 ].

DC (304 mg initial value) represents the dietary cholesterol and it was used in simulations
with different values. The equations of model include theoretical predefined values of parameters and
experimental fitting constants [8]. Solution is made using Runge-Kutta method, and the plotting time
is measured in days.
Two mechanisms are taken into account for estimation dysregulation of cholesterol
metabolism with age (rise of rise of LDL-C with age): intestinal cholesterol absorption (k6) and rate of
removal of LDL-C from the plasma (simulated by variations of the constant khr). In order to estimate
the influence of these factors (even the mechanism is not completely understood), the increasing and
decreasing is made in percent, the measured evolutions being made in interval 20-65 years.
 III. THE SIMULATION TOOL FOR PEDAGOGICAL USE

The first scenario is no mdiet (mdiet = 0), and the system will have small oscillations with around
a stable value due to mechanism or regulation (figure 2). The second scenario is using the model 1
with modification in dietary intake (figure 3). In the case of multiple curves, the values separated by
‘;’ tag are parsed and plotted on the same graphic.

Figure no. 3. Simulation of cholesterol level changes (mdiet = 0), model 1

Figure no. 4. Simulation for incresing/decreasing parameter m out (-10%, -20%,+10%), model 1

Figure no. 5. Simulation of schema of treatment with Statin, model 1 (60 days no treatment,
30 treatment, and discontinuation)
 Figure no. 6. Model 2, GUI (Graphic User Interface) for k parameters

Figure no. 7. Response of model 2 to dietary cholesterol

Figure no. 8 Simulation of relationship between LDL-C cholesterol and age by modification
of the number of epatic low density lipoprotein receptors (HLDLRs)
 The first model takes simulates a treatment with statin, a common treatment to decrease the
“bad cholesterol”, LDL-C, applied after 60 days and suspended after 30 days. The evolution of LDL-C
is showed in figure 4.
The second two scenarios take into account the model 2. Two plots are exemplified, the
simulation for intake of dietary cholesterol (figure 6) and one of the two mentioned possibilities [8] the
increasing of LDL-C with age by HLDLRs. The other possibility, the modification of k hrs (the number
of synthesis of hepatic LDL receptors) is also provided by proposed educational tool.

IV. CONCLUSIONS
An educational tool for interactive exercise is provided for the second year biomedical
engineering students. The tool ask two session of laboratories because the second model is more
complicated and the mechanisms of whole-body model of cholesterol metabolism. In the second
model, the biliary cholesterol (gallbladder) is included, along with simulation of aging.
The tool is under development yet and the future work is focused on append the gallbladder
and a correction function for aging in order to improve the simpler model 1.

Reference Text and Citations

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