Resilience of Cholesterol Concentration to a Wide Range of Mutations in the Cell

The study of normal and pathological states of the gene network regulating cholesterol biosynthesis in the cell is a topical problem. Impairments of this system play a key role in the development of hypercholesterolemia and atherosclerosis of humans and various animals. Knowledge of the behavior of this system under various conditions is necessary to develop optimal strategies for correcting various pathologies while taking into account the genotype-specific distinctions of individuals and the targets for pharmacological regulation. The model simulating cholesterol biosynthesis in the cell and its exchange with blood plasma cholesterol developed earlier using a generalized chemical kinetic approach was used for the analysis of a mutational portrait of this system. The sensitivity of the stationary content of free cholesterol to mutational changes in the rates of molecular processes running within the gene network was analyzed. The resilience of the free cholesterol concentration to a wide range of mutations in the gene network was demonstrated. In addition, it was shown that the mutations hitting regulatory processes changed the stationary content of free cholesterol to the largest degree.

[1]  X. Hua,et al.  SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis , 1994, Cell.

[2]  A. Soutar.  Familial hypercholesterolaemia and LDL receptor mutations , 1992, Journal of internal medicine.

[3]  O. A. Podkolodnaya,et al.  Generalized Chemokinetic Method for Gene Network Simulation , 2001, Molecular Biology.

[4]  P. Edwards,et al.  Synergistic Binding of Sterol Regulatory Element-binding Protein and NF-Y to the Farnesyl Diphosphate Synthase Promoter Is Critical for Sterol-regulated Expression of the Gene* , 1996, The Journal of Biological Chemistry.

[5]  J. Rosenfeld,et al.  A Direct Role for Sterol Regulatory Element Binding Protein in Activation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Gene (*) , 1996, The Journal of Biological Chemistry.

[6]  F. Field,et al.  Regulation of Sterol Regulatory Element-binding Proteins in Hamster Intestine by Changes in Cholesterol Flux* , 2001, The Journal of Biological Chemistry.

[7]  M. Brown,et al.  The low-density lipoprotein pathway and its relation to atherosclerosis. , 1977, Annual review of biochemistry.

[8]  A. Beaudet,et al.  Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. , 1975, The Journal of biological chemistry.

[9]  Timothy F. Osborne,et al.  Multiple Sequence Elements are Involved in the Transcriptional Regulation of the Human Squalene Synthase Gene* , 1997, The Journal of Biological Chemistry.

[10]  H. Hobbs,et al.  The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. , 1990, Annual review of genetics.