A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway

JOURNAL OF THEORETICAL BIOLOGY

卷:349

Article

Bhattacharya, Bonhi S.¹  Sweby, Peter K.¹  Minihane, Anne-Marie²  Jackson, Kim G.^3,5  Tindall, Marcus J.^1,4,5 

[1] Univ Reading, Dept Math & Stat, Reading RG6 6AX, Berks, England

[2] Univ E Anglia, Norwich Med Sch, Dept Nutr, Norwich NR4 7TJ, Norfolk, England

[3] Univ Reading, Dept Food & Nutr Sci, Reading RG6 6AP, Berks, England

[4] Univ Reading, Sch Biol Sci, Reading RG6 6AJ, Berks, England

[5] Univ Reading, Inst Cardiovasc & Metab Res, Reading RG6 6AA, Berks, England

关键词: Genetic regulation;    Transcription factor;    Nonlinear ordinary differential equation;    SREBP-2;   

DOI  :  10.1016/j.jtbi.2014.01.013

来源: Elsevier

【 摘 要 】

Cholesterol is one of the key constituents for maintaining the cellular membrane and thus the integrity of the cell itself. In contrast high levels of cholesterol in the blood are known to be a major risk factor in the development of cardiovascular disease. We formulate a deterministic nonlinear ordinary differential equation model of the sterol regulatory element binding protein 2 (SREBP-2) cholesterol genetic regulatory pathway in a hepatocyte. The mathematical model includes a description of genetic transcription by SREBP-2 which is subsequently translated to mRNA leading to the formation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a main regulator of cholesterol synthesis. Cholesterol synthesis subsequently leads to the regulation of SREBP-2 via a negative feedback formulation. Parameterised with data from the literature, the model is used to understand how SREBP-2 transcription and regulation affects cellular cholesterol concentration. Model stability analysis shows that the only positive steady-state of the system exhibits purely oscillatory, damped oscillatory or monotic behaviour under certain parameter conditions. In light of our findings we postulate how cholesterol homeostasis is maintained within the cell and the advantages of our model formulation are discussed with respect to other models of genetic regulation within the literature. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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