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Model of cholesterol biosynthesis regulation

Cholesterol, an amphipathic lipid, is an essential structural component of the cell membrane and outer layer of lipoproteins of blood plasma. Simultaneously, cholesterol is a precursor of several other steroids, namely, corticosteroids, sex hormones, bile acids, and vitamin D. Cholesterol is synthesized from acetyl-CoA, and its major fraction in the blood plasma resides in the low-density lipoproteins (LDL). Cholesterol is removed from tissues with involvement of high-density lipoproteins (HDL) to be transported into the liver and transformed there into bile acids. In pathology, cholesterol is a factor causing atherosclerosis of vital cerebral arteries, heart muscle, and other organs. A high value of the LDL cholesterol to HDL cholesterol ratio in the plasma is observed during coronary atherosclerosis. This determines a great biomedical and applied importance of studying cholesterol turnover in the organism.

The gene network regulating intracellular cholesterol biosynthesis is now studied in sufficient detail. Data on its performance patterns are accumulated in the GeneNet database. Acetyl-CoA is the source of all the carbon atoms of the cholesterol molecule. Cholesterol biosynthesis pathway comprises numerous stages and is controlled by a variety of enzymes, including HMG-CoA reductase, farnesyl diphosphate synthetase, and squalene synthetase. Syntheses of the enzymes listed are activated by SREBP (sterol regulatory element-binding protein). In turn, the activity of SREBP depends on the intracellular cholesterol concentration in a negative feedback mode: the lower is the concentration of metabolically active cholesterol in the cell, the higher is the SREBP activity.

We have developed a model of functional dynamics of this gene network. The model describes all the stages of cholesterol biosynthesis shown in GeneNet database. In addition, the model describes the mechanisms underlying the interchange of intracellular and blood cholesterols. Negative feedbacks whereby cholesterol exerts the control over its own synthesis and synthesis of LDL receptors at the transcription level [Wang et al., 1994] are also considered. Totally, the model comprises 65 elementary processes. The model of performance dynamics of this gene network described in the GeneNet database contains 40 products (dynamic variables). Brief descriptions of the gene network objects presented in the model as dynamic variables given in the table.

Table. The objects of gene network of cholesterol biosynthesis regulation presented in the models as dynamic variable

Gene network object name Brief description of dynamic variable
acetyl-CoA Concentration (molecules/cell) of acetyl-CoA
acetoacethyl-CoA Concentration (molecules/cell) of acetoacethyl-CoA
HMGCS Concentration (molecules/cell) of 3-hydroxy-3-methylglutaryl coenzyme A synthase
HMG-CoA Concentration (molecules/cell) of 3-hydroxy-3-methylglutaryl coenzyme A
HMGR Concentration (molecules/cell) of 3-hydroxy-3-methylglutaryl-CoA reductase
Mevalonic acid Concentration (molecules/cell) of mevalonic acid
Mevalonic acid 5-phosphate Concentration (molecules/cell) of mevalonic acid 5-phosphate
5-Diphosphomevalonate Concentration (molecules/cell) of 5-Diphosphomevalonate
Isopentenyl diphosphate Concentration (molecules/cell) of isopentenyl diphosphate
Dimethylallyl diphosphate Concentration (molecules/cell) of dimethylallyl diphosphate
Geranyl diphosphate Concentration (molecules/cell) of geranyl diphosphate
FPPS Concentration (molecules/cell) of farnesyl diphosphate synthase
Farnesyl diphosphate Concentration (molecules/cell) of farnesyl diphosphate
Presqualene diphosphate Concentration (molecules/cell) of presqualene diphosphate
SS Concentration (molecules/cell) of squalene synthase
Squalene Concentration (molecules/cell) of squalene
Cholesterol Concentration (molecules/cell) of free pool of intracellular cholesterol
LDL Concentration (molecules/cell) of low density lipoprotein (LDL)
LDLRm Concentration (molecules/cellular membrane) of free membrane LDL receptor
LDLRLDLm Concentration (molecules/cellular membrane) of LDL receptor bound to LDL on the cell surface
LDLRLDLi Concentration (molecules/cell) of LDL receptor bound to LDL in the cell
LDLRi Concentration (molecules/cell) of free intracellular LDL receptor
preSREBP1 Concentration (molecules/cell) of sterol regulatory element-binding protein-1 precursor
SRP Concentration (molecules/cell) of sterol regulated protease
SREBP1 Concentration (molecules/cell) of sterol regulatory element-binding protein-1
SREBP1d Concentration (molecules/cell) of homodimer of sterol regulatory element-binding protein-1
ACAT_i Concentration (molecules/cell) of acyl-CoA: cholesterol acyltransferase inactive
ACAT_a Concentration (molecules/cell) of acyl-CoA: cholesterol acyltransferase active
Cholesterol ester Concentration (molecules/cell) of cholesterol ester
Hydrolase Concentration (molecules/cell) of hydrolase cholesterol ester

The model contains 93 constants. Values of a number of constants were assessed using the relevant published data [Gil et al., 1981; Kleinsek et al, 1979; Reed et al., 1975; Rokosz et al., 1994; Huth et al., 1975; Sasiak and Rilling, 1988; Croteau and Purkett, 1989; Barnard and Popjak, 1981; Balliano et al., 1992; Chang et al., 1998; Lundeen and Savage, 1990]. The rest parameters were determined through numerical experiments [Ratushny et al., 2000à] using quantitative and qualitative characteristics known the literature as criteria of their adequacies. This model allows the equilibrium state of the biosystem to be calculated. The equilibrium persists while the environmental conditions remain constant. If they change, for example, the content of LDL particles in blood plasma increases twofold, the system equilibrium is disturbed (Fig. 5). Consequently, the concentration of receptors bound to LDL increases (e); unbound, decreases (d). Intracellular concentrations of free cholesterol (a) and its esters (c) increase, etc. Unless a new intervention occurs, the negative feedbacks restore the initial state of the system: the initial cholesterol concentration in the cell reestablishes in approximately 3h, while the overall initial state of the system restores in 10- 15 h.

Figure 5


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