A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction.
The cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalysing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses.
Division of Pathway Medicine, University of Edinburgh Medical School, Chancellor's Building, 49 Little France Crescent, Edinburgh, Scotland, United Kingdom. s.watterson@ed.ac.uk
Steven
S
Watterson
Maria Luisa
ML
Guerriero
Mathieu
M
Blanc
Alexander
A
Mazein
Laurence
L
Loewe
Kevin A
KA
Robertson
Holly
H
Gibbs
Guanghou
G
Shui
Markus R
MR
Wenk
Jane
J
Hillston
Peter
P
Ghazal
D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007109:Immunity / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008954:Models, Biological; D018146:Muromegalovirus / Q000502:physiology; D015203:Reproducibility of Results
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007371:Interferon-gamma; D002784:Cholesterol