A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD.

In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the build-up of glucose intermediates was less severe in the periportal hepatocyte compartments. Secondly, the periportal zonation of the enzymes mediating ß-oxidation and oxidative phosphorylation resulted in excess fats being metabolised more rapidly in the periportal hepatocyte compartments. Finally, the pericentral expression of de novo lipogenesis contributed to pericentral steatosis when additionally simulating the increase in sterol-regulatory element binding protein 1c (SREBP-1c) seen in NAFLD patients in vivo. The hepatic triglyceride concentration was predicted to be most sensitive to inter-individual variation in the activity of enzymes which, either directly or indirectly, determine the rate of free fatty acid (FFA) oxidation. The concentration was most strongly dependent on the rate constants for ß-oxidation and oxidative phosphorylation. It also showed moderate sensitivity to the rate constants for processes which alter the allosteric inhibition of ß-oxidation by acetyl-CoA. The predominant sinusoidal location of steatosis meanwhile was most sensitive variations in the zonation of proteins mediating FFA uptake or triglyceride release as very low density lipoproteins (VLDL). Neither the total hepatic concentration nor the location of steatosis showed strong sensitivity to variations in the lipogenic rate constants.

Defining a quantitative framework for evaluation and optimisation of the environmental impacts of mega-event projects.

This paper presents a novel quantitative methodology for the evaluation and optimisation of the environmental impacts of the whole life cycle of a mega-event project: construction and staging the event and post-event site redevelopment and operation. Within the proposed framework, a mathematical model has been developed that takes into account greenhouse gas (GHG) emissions resulting from use of transportation fuel, energy, water and construction materials used at all stages of the mega-event project. The model is applied to a case study - the London Olympic Park. Three potential post-event site design scenarios of the Park have been developed: Business as Usual (BAU), Commercial World (CW) and High Rise High Density (HRHD). A quantitative summary of results demonstrates that the highest GHG emissions associated with the actual event are almost negligible compared to those associated with the legacy phase. The highest share of emissions in the legacy phase is attributed to embodied emissions from construction materials (almost 50% for the BAU and HRHD scenarios) and emissions resulting from the transportation of residents, visitors and employees to/from the site (almost 60% for the CW scenario). The BAU scenario is the one with the lowest GHG emissions compared to the other scenarios. The results also demonstrate how post-event site design scenarios can be optimised to minimise the GHG emissions. The overall outcomes illustrate how the proposed framework can be used to support decision making process for mega-event projects planning.

Computational Modeling of Fructose Metabolism and Development in NAFLD.

Non-alcohol fatty liver disease (NAFLD) is a common disorder that has increased in prevalence 20-fold over the last three decades. It covers a spectrum of conditions resulting from excess lipid accumulation in the liver without alcohol abuse. Among all the risk factors, over-consumption of fructose has been repeatedly reported in both clinical and experimental studies to be highly associated with the development of NAFLD. However, studying in vivo systems is complicated, time consuming and expensive. A detailed kinetic model of fructose metabolism was constructed to investigate the metabolic mechanisms whereby fructose consumption can induce dyslipidaemia associated with NAFLD and to explore whether the pathological conditions can be reversed during the early stages of disease. The model contains biochemical components and reactions identified from the literature, including ~120 parameters, 25 variables, and 25 first order differential equations. Three scenarios were presented to demonstrate the behavior of the model. Scenario one predicts the acute effects of a change in carbohydrate input in lipid profiles. The results present progressive triglyceride accumulations in the liver and plasma for three diets. The rate of accumulation was greater in the fructose diet than that of the mixed or glucose only models. Scenario two explores the variability of metabolic reaction rate within the general population. Sensitivity analysis reveals that hepatic triglyceride concentration is most sensitive to the rate constant of pyruvate kinase and fructokinase. Scenario three tests the effect of one specific inhibitor that might be potentially administered. The simulations of fructokinase suppression provide a good model for potentially reversing simple steatosis induced by high fructose consumption, which can be corroborated by experimental studies. The predictions in these three scenarios suggest that the model is robust and it has sufficient detail to present the kinetic relationship between fructose and lipid in the liver.

Robustness of the p53 network and biological hackers.

The p53 protein interaction network is crucial in regulating the metazoan cell cycle and apoptosis. Here, the robustness of the p53 network is studied by analyzing its degeneration under two modes of attack. Linear Programming is used to calculate average path lengths among proteins and the network diameter as measures of functionality. The p53 network is found to be robust to random loss of nodes, but vulnerable to a targeted attack against its hubs, as a result of its architecture. The significance of the results is considered with respect to mutational knockouts of proteins and the directed attacks mounted by tumour inducing viruses.

Life cycle assessment of integrated waste management systems for alternative legacy scenarios of the London Olympic Park.

This paper presents the results of the life cycle assessment (LCA) of 10 integrated waste management systems (IWMSs) for 3 potential post-event site design scenarios of the London Olympic Park. The aim of the LCA study is to evaluate direct and indirect emissions resulting from various treatment options of municipal solid waste (MSW) annually generated on site together with avoided emissions resulting from energy, materials and nutrients recovery. IWMSs are modelled using GaBi v6.0 Product Sustainability software and results are presented based on the CML (v.Nov-10) characterisation method. The results show that IWMSs with advanced thermal treatment (ATT) and incineration with energy recovery have the lowest Global Warming Potential (GWP) than IWMSs where landfill is the primary waste treatment process. This is due to higher direct emissions and lower avoided emissions from the landfill process compared to the emissions from the thermal treatment processes. LCA results demonstrate that significant environmental savings are achieved through substitution of virgin materials with recycled ones. The results of the sensitivity analysis carried out for IWMS 1 shows that increasing recycling rate by 5%, 10% and 15% compared to the baseline scenario can reduce GWP by 8%, 17% and 25% respectively. Sensitivity analysis also shows how changes in waste composition affect the overall result of the system. The outcomes of such assessments provide decision-makers with fundamental information regarding the environmental impacts of different waste treatment options necessary for sustainable waste management planning.

Analysis of metabolic networks using a pathway distance metric through linear programming.

The solution of the shortest path problem in biochemical systems constitutes an important step for studies of their evolution. In this paper, a linear programming (LP) algorithm for calculating minimal pathway distances in metabolic networks is studied. Minimal pathway distances are identified as the smallest number of metabolic steps separating two enzymes in metabolic pathways. The algorithm deals effectively with circularity and reaction directionality. The applicability of the algorithm is illustrated by calculating the minimal pathway distances for Escherichia coli small molecule metabolism enzymes, and then considering their correlations with genome distance (distance separating two genes on a chromosome) and enzyme function (as characterised by enzyme commission number). The results illustrate the effectiveness of the LP model. In addition, the data confirm that propinquity of genes on the genome implies similarity in function (as determined by co-involvement in the same region of the metabolic network), but suggest that no correlation exists between pathway distance and enzyme function. These findings offer insight into the probable mechanism of pathway evolution.