scholarly journals Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

2017 ◽  
Vol 174 (23) ◽  
pp. 4362-4382 ◽  
Author(s):  
Helen E Benson ◽  
Steven Watterson ◽  
Joanna L Sharman ◽  
Chido P Mpamhanga ◽  
Andrew Parton ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Systems Pharmacology ◽  
Cholesterol Biosynthesis Pathway ◽  
Therapy Development

scholarly journals FBXW7 regulates endothelial barrier function by suppression of the cholesterol synthesis pathway and prenylation of RhoB

2019 ◽  
Vol 30 (5) ◽  
pp. 607-621 ◽  
Author(s):  
Manon C. A. Pronk ◽  
Jisca Majolée ◽  
Anke Loregger ◽  
Jan S. M. van Bezu ◽  
Noam Zelcer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Barrier Function ◽  
Rho Gtpases ◽  
Umbilical Vein ◽  
Cholesterol Biosynthesis ◽  
Endothelial Barrier ◽  
Biosynthesis Pathway ◽  
Endothelial Barrier Function ◽  
Cholesterol Biosynthesis Pathway

Rho GTPases control both the actin cytoskeleton and adherens junction stability and are recognized as essential regulators of endothelial barrier function. They act as molecular switches and are primarily regulated by the exchange of GDP and GTP. However, posttranslational modifications such as phosphorylation, prenylation, and ubiquitination can additionally alter their localization, stability, and activity. F-box proteins are involved in the recognition of substrate proteins predestined for ubiquitination and subsequent degradation. Given the importance of ubiquitination, we studied the effect of the loss of 62 members of the F-box protein family on endothelial barrier function in human umbilical vein endothelial cells. Endothelial barrier function was quantified by electrical cell impedance sensing and macromolecule passage assay. Our RNA interference–based screen identified FBXW7 as a key regulator of endothelial barrier function. Mechanistically, loss of FBXW7 induced the accumulation of the RhoB GTPase in endothelial cells, resulting in their increased contractility and permeability. FBXW7 knockdown induced activation of the cholesterol biosynthesis pathway and changed the prenylation of RhoB. This effect was reversed by farnesyl transferase inhibitors and by the addition of geranylgeranyl pyrophosphate. In summary, this study identifies FBXW7 as a novel regulator of endothelial barrier function in vitro. Loss of FBXW7 indirectly modulates RhoB activity via alteration of the cholesterol biosynthesis pathway and, consequently, of the prenylation status and activity of RhoB, resulting in increased contractility and disruption of the endothelial barrier.

scholarly journals A mathematical model of the mevalonate cholesterol biosynthesis pathway

2018 ◽  
Vol 443 ◽  
pp. 157-176 ◽  
Author(s):  
Frances Pool ◽  
Richard Currie ◽  
Peter K. Sweby ◽  
José Domingo Salazar ◽  
Marcus J. Tindall
Keyword(s):  
Mathematical Model ◽  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Cholesterol Biosynthesis Pathway

scholarly journals SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease

2020 ◽  
Author(s):  
Giulia Birolini ◽  
Gianluca Verlengia ◽  
Francesca Talpo ◽  
Claudia Maniezzi ◽  
Lorena Zentilin ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Nuclear Translocation ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Cholesterol Biosynthesis Pathway

AbstractBrain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.

scholarly journals OTME-15. Physical Confinement Induces Diverse Transcriptomic Changes and Chemoresistance in Migrating Glioblastoma Cells

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii16-ii16
Author(s):  
James Battiste ◽  
Anish Babu ◽  
Rachel Sharp ◽  
Sydney Scott ◽  
Ian Dunn ◽  
...  
Keyword(s):  
Cell Cycle ◽  
White Matter ◽  
Cell Cycle Regulation ◽  
Cholesterol Biosynthesis ◽  
Microfluidic Channels ◽  
Biosynthesis Pathway ◽  
Confined Spaces ◽  
Cholesterol Biosynthesis Pathway ◽  
Transcriptomic Changes ◽  
Cycle Regulation

Abstract Glioblastoma multiforme (GBM) cells migrating in physically confined environments are affected by mechanical stress that potentially lead to transcriptomic changes. To simulate those stresses, microfluidic channels were made with micro-patterned polydimethylsiloxane (PDMS) replicating the physical microenvironment of white matter tracts by confining the cells in linear channels similar to the space between axons. We employed a combination of microarray transcriptomic profiling and single cell-sequencing analyses to investigate cells undergoing linear confined space migration (LCSM). GBM cells spontaneously migrate through confined spaces along 5x5 mm (height/width) microfluidic channels, 0.5 to 5 mm in length. Our previous studies demonstrated that cells migrating in LCSM are more resistant to treatment with temozolomide than the same cells growing in standard monolayer culture (SMC). Cells in confined migration evaluated by microarray-based transcriptomic profiling demonstrated that linear confined migration induces increased expression in pathways involving angiogenesis, cell adhesion, cell motility, DNA damage repair, extracellular matrix structure, HIF1α, and others. Single cell transcriptomic analysis could identify GBM cells in different migratory states (LCSM vs. SMC), and similar pathways were seen upregulated with additional changes in cholesterol biosynthesis pathways and cell cycle regulation pathways. Trajectory Inference aligned single cells according to changes in migration status and demonstrated transcript changes during LCSM were progressive but generally reversible on return to SMC. Pathway analyses showed alterations in the cholesterol biosynthesis pathway and cell cycle regulation in cell clusters of confined migrating cells. Molecular studies confirmed that cholesterol biosynthesis pathway regulatory genes (SQLE, MVD, and HMGCR) are upregulated during LCSM. Expression analysis demonstrated increased G1 phase delay in confined migrating cells (LCSM) confirmed by FUCCI expression analysis. We propose that migration in linear confined spaces like white matter structures produces significant transcriptome changes that produce chemoresistance as a new mechanism for treatment resistance of Glioblastoma.

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

2013 ◽  
Author(s):  
Steven Watterson ◽  
Maria-Luisa Guerriero ◽  
Mathieu Blanc ◽  
Alexander Mazein ◽  
Laurence Loewe ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Enzyme Regulation ◽  
Murine Cytomegalovirus ◽  
Mrna Levels ◽  
Cellular Interactions ◽  
Biosynthesis Pathway ◽  
Down Regulation ◽  
Coordinate Regulation ◽  
Cholesterol Biosynthesis Pathway ◽  
Single Enzyme

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 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 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.

scholarly journals New Inhibitory Effect of Latilactobacillus sakei UONUMA on the Cholesterol Biosynthesis Pathway in Human HepG2 Cells

2021 ◽  
Vol 44 (4) ◽  
pp. 485-493
Author(s):  
Miho Ohta-Shimizu ◽  
Fumiko Fuwa ◽  
Eriko Tomitsuka ◽  
Toshikazu Nishiwaki ◽  
Kotaro Aihara ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Cholesterol Biosynthesis ◽  
Inhibitory Effect ◽  
Biosynthesis Pathway ◽  
Cholesterol Biosynthesis Pathway

scholarly journals The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Esperanza Perucha ◽  
Rossella Melchiotti ◽  
Jack A Bibby ◽  
Wing Wu ◽  
Klaus Stensgaard Frederiksen ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Th1 Cells ◽  
Biosynthesis Pathway ◽  
Cholesterol Biosynthesis Pathway
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