Integration of Genome Scale Metabolic Networks and Gene Regulation of Metabolic Enzymes With Physiologically Based Pharmacokinetics

Maldonado, Elaina M.; Leoncikas, Vytautas; Fisher, Ciarán; Moore, J. Bernadette; Plant, Nick; Kierzek, Andrzej M.

doi:10.1002/psp4.12230

Cited by 19 publications

(20 citation statements)

References 53 publications

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“…individual enzymes in a network). Later steps may seek to become quantitative in the sense that we provide equations for the interactions and then seek to parameterise them (Maldonado et al ., ). At present, we are still at the very first step or highest level, i.e.…”

Section: Introductionmentioning

confidence: 97%

No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

Kell

2018

Biological Reviews

108

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Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre‐eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress‐induced iron dysregulation, and (ii) its ability to awaken dormant, non‐replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.

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Section: Introductionmentioning

confidence: 97%

No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

Kell

2018

Biological Reviews

108

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“…Increasingly, GSMNs are being integrated with detailed gene regulatory and/or physiologically based pharmaco/toxico-kinetic models in the emergent fields of quantitative systems pharmacology/toxicology. 23 …”

Section: Introductionmentioning

confidence: 99%

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

et al. 2018

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Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD.

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“…3(a)) and flux balance analysis is limited in being static and not reflecting the dynamic metabolic response to altered cell signalling. A very active area of systems research is focused on developing novel tools and algorithms for integrating and simulating models at multiple scales and linking GSMNs to gene regulatory networks and/or physiologically based pharmacokinetic models in systems pharmacology/toxicology and kinetic signalling networks (140)(141)(142) .…”

Section: Modelling Liver Metabolismmentioning

confidence: 99%

“…Building on their previous work establishing the use of quasi-steady state Petri nets to integrate and simulate gene regulatory networks and/or physiologically based pharmacokinetic models with constraint-based GSMNs (140)(141)(142) ; the group has developed novel multiscale models to predict the hepatocyte's response to fat and sugar (92) . In one case, from experimental -omics data and the literature, they manually curated a comprehensive network reconstruction of the PPARα regulome.…”

Section: Application Of Systems Approaches To Non-alcoholic Fatty LIVmentioning

confidence: 99%

From sugar to liver fat and public health: systems biology driven studies in understanding non-alcoholic fatty liver disease pathogenesis

Moore

2019

Proc. Nutr. Soc.

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Non-alcoholic fatty liver disease (NAFLD) is now a major public health concern with an estimated prevalence of 25-30 % of adults in many countries. Strongly associated with obesity and the metabolic syndrome, the pathogenesis of NAFLD is dependent on complex interactions between genetic and environmental factors that are not completely understood. Weight loss through diet and lifestyle modification underpins clinical management; however, the roles of individual dietary nutrients (e.g. saturated and n-3 fatty acids; fructose, vitamin D, vitamin E) in the pathogenesis or treatment of NAFLD are only partially understood. Systems biology offers valuable interdisciplinary methods that are arguably ideal for application to the studying of chronic diseases such as NAFLD, and the roles of nutrition and diet in their molecular pathogenesis. Although present in silico models are incomplete, computational tools are rapidly evolving and human metabolism can now be simulated at the genome scale. This paper will review NAFLD and its pathogenesis, including the roles of genetics and nutrition in the development and progression of disease. In addition, the paper introduces the concept of systems biology and reviews recent work utilising genome-scale metabolic networks and developing multi-scale models of liver metabolism relevant to NAFLD. A future is envisioned where individual genetic, proteomic and metabolomic information can be integrated computationally with clinical data, yielding mechanistic insight into the pathogenesis of chronic diseases such as NAFLD, and informing personalised nutrition and stratified medicine approaches for improving prognosis.

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Integration of Genome Scale Metabolic Networks and Gene Regulation of Metabolic Enzymes With Physiologically Based Pharmacokinetics

Cited by 19 publications

References 53 publications

No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

From sugar to liver fat and public health: systems biology driven studies in understanding non-alcoholic fatty liver disease pathogenesis

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