A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway.
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.
Department of Mathematics and Statistics, University of Reading, Whiteknights, Reading RG6 6AX, UK.
Bonhi S
BS
Bhattacharya
Department of Mathematics and Statistics, University of Reading, Whiteknights, Reading RG6 6AX, UK.
Peter K
PK
Sweby
Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK.
Anne-Marie
AM
Minihane
Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading RG6 6AP, UK; Institute of Cardiovascular and Metabolic Research, University of Reading, Whiteknights, Reading RG6 6AA, UK.
Kim G
KG
Jackson
Department of Mathematics and Statistics, University of Reading, Whiteknights, Reading RG6 6AX, UK; School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6AJ, UK; Institute of Cardiovascular and Metabolic Research, University of Reading, Whiteknights, Reading RG6 6AA, UK. Electronic address: m.tindall@reading.ac.uk.
Marcus J
MJ
Tindall
D053898:Biosynthetic Pathways / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol
Genetic regulation; Nonlinear ordinary differential equation; SREBP-2; Transcription factor