Modeling cholesterol metabolism by gene expression profiling in the hippocampus

Abstract

An important part of the challenge of building models of biochemical reactions is determining reaction rate constants that transform substrates into products. We present a method to derive enzymatic kinetic values from mRNA expression levels for modeling biological networks without requiring further tuning. The core metabolic reactions of cholesterol in the brain, particularly in the hippocampus, were simulated. To build the model the baseline mRNA expression levels of genes involved in cholesterol metabolism were obtained from the Allen Mouse Brain Atlas. The model is capable of replicating the trends of relative cholesterol levels in Alzheimer’s and Huntington’s diseases; and reliably simulated SLOS, desmosterolosis, and Dhcr14/Lbr knockout studies. A sensitivity analysis correctly uncovers the Hmgcr, Idi2 and Fdft1 sites that regulate cholesterol homeostasis. Overall, our model and methodology can be used to pinpoint key reactions, which, upon manipulation, may predict altered cholesterol levels and reveal insights into potential drug therapy targets under diseased conditions.

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

“…However, this may not be enough to conclude that the HD group had a cognitive deficit. Similar and more conclusive results confirmed our hypothesis in a study on both LDL receptor (LDLr) rodents and C57BL/6 6 Iran Red Crescent Med J. 2016; 18(12):e35677.…”

“…Recent studies have also shown that APP processing by BACE1 is sensitive to cholesterol levels. Aβ deposits trigger several pathologic pathways involved in neuronal cell death (6). As the uptake of cholesterol from the circulating blood is prevented by an intact BBB, the brain is dependent on in situ synthesis of cholesterol (7)(8)(9).…”

In Vivo and In Silico Evidence: Hippocampal Cholesterol Metabolism Decreases with Aging and Increases with Alzheimers Disease -- Modeling Brain Aging and Disease

“…A schematic diagram of the cholesterol synthesis and degradation pathways, and the reactions, used in this TTM TM Model are published [38]. Cholesterol synthesis I is found in adult brain; pathway III is prevalent during fetal and postnatal periods [7].…”

“…Our current Transcriptome To Metabolome TM Model simulates 16 core metabolic pathways that include 220 species (metabolites), 295 reactions, and over 250 genes. The gene expression levels from microarray data sets were used to derive the kinetic parameters for the reactions in the TTM TM Biosimulation Model [37,38] for each study group as per the original reports [1,2] . The secondary data sets, i.e., species levels and reaction flux values were exported by COPASI into tab-delimited text files.…”

“…Only in silico approaches allow the sensitivities analyses [26,38] that can readily identify candidate biomarkers and targets for interventions in this drug discovery process; such targets can be economically tested, first, within the same in silico model to determine efficacy, toxicity, and dosing; before any laboratory or clinical testing begins. Before these far reaching goals can be achieved for AD, we must first ask specific questions about the changes in metabolism and other biological pathways that occur in brain tissue and neurons with both normal aging and with progression of the AD pathophysiology [3,4,8,12,13,19,22,23,30].…”