A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction

Abstract

Graphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC=\"FIGDIR/small/000380_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@197f26org.highwire.dtl.DTLVardef@1eac3f3org.highwire.dtl.DTLVardef@1e698f1org.highwire.dtl.DTLVardef@42fb4b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe model the cholesterol biosynthesis pathway and its regulation\nC_LIO_LIThe innate immune response leads to a suppression of flux through the pathway\nC_LIO_LIStatin inhibitors show a different mode of suppression to the immune response\nC_LIO_LIStatin inhibitor suppression is less robust and less specific than immune suppression\nC_LI\n\nAsbtractThe 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 catalyzing 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 infection or treated with IFN{gamma}, 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.