Dataset Information

Computational Modeling of Fructose Metabolism and Development in NAFLD.

ABSTRACT: 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.

SUBMITTER: Liao Y

PROVIDER: S-EPMC7388684 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Computational Modeling of Fructose Metabolism and Development in NAFLD.

Liao Yunjie Y Davies Nathan A NA Bogle I David L IDL

Frontiers in bioengineering and biotechnology 20200722

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 <i>in vivo</i> systems is complicated, time consuming an ...[more]

PMID: 32775322

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Project description: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 β-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 β-oxidation and oxidative phosphorylation. It also showed moderate sensitivity to the rate constants for processes which alter the allosteric inhibition of β-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.

Project description:The metal complexes can demonstrate various interesting biological activities in the human body. However, the role of certain metal ions for specific cell activities is still subject to debate. This study is aimed at comparing the thermochemical properties of neotame (artificial sweetener) and α, β-fructose in gas phase and water medium. The interaction of α and β-fructose, neotame with monovalent and divalent metal ions was studied and comprehended by density functional theory (DFT) using B3LYP functional, 6-311 + G (d, p) and D3 basis set. Metal ion affinities (MIA) values depicted that ionic radius of metal ions played an important role in the interaction of α, β-fructose and neotame. The ∆G parameter was calculated to predict and understand the interaction of metal ions with α and β-fructose, neotame. The results suggested that the presence of hydroxyl groups and oxygen atoms in sugar molecules acted as preferred sites for the binding and interaction of mono and divalent ions. For the first time computational study has been introduced in the present study to review the progress in the application of metal binding with sugar molecules especially with neotame. Moreover, voltammetric behaviour of neotame-Zn2+ was studied using cyclic and differential pulse voltammetry. The obtained results suggest that the peak at -1.13 V is due to the reduction of Zn2+ in 0.1 M phosphate buffer medium at pH 5.5. Whereas, addition of 6-fold higher concentration of neotame to the ZnCl2.2H2O resulted in a new irreversible cathodic peak at -0.83, due to the reduction of neotame-Zn2+ complex. The Fourier transform infrared spectroscopy (FTIR) results indicates that the β-amino group (-NH) and carboxyl carbonyl (-C = O) groups of neotame is participating in the chelation process, which is further supported by DFT studies. The findings of this study identify the efficient chelation factors as major contributors into metal ion affinities, with promising possibilities to determine important biological processes in cell wall and glucose transmembrane transport.

Dataset Information

Computational Modeling of Fructose Metabolism and Development in NAFLD.

Publications

Computational Modeling of Fructose Metabolism and Development in NAFLD.

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