119 research outputs found
Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones
Being the central metabolic organ of vertebrates, the liver possesses the largest repertoire of metabolic enzymes among all tissues and organs. Almost all metabolic pathways are resident in the parenchymal cell, hepatocyte, but the pathway capacities may largely differ depending on the localization of hepatocytes within the liver acinus-a phenomenon that is commonly referred to as metabolic zonation. Metabolic zonation is rather dynamic since gene expression patterns of metabolic enzymes may change in response to nutrition, drugs, hormones and pathological states of the liver (e.g., fibrosis and inflammation). This fact has to be ultimately taken into account in mathematical models aiming at the prediction of metabolic liver functions in different physiological and pathological settings. Here we present a spatially resolved kinetic tissue model of hepatic glucose metabolism which includes zone-specific temporal changes of enzyme abundances which are driven by concentration gradients of nutrients, hormones and oxygen along the hepatic sinusoids. As key modulators of enzyme expression we included oxygen, glucose and the hormones insulin and glucagon which also control enzyme activities by cAMP-dependent reversible phosphorylation. Starting with an initially non-zonated model using plasma profiles under fed, fasted and diabetic conditions, zonal patterns of glycolytic and gluconeogenetic enzymes as well as glucose uptake and release rates are created as an emergent property. We show that mechanisms controlling the adaptation of enzyme abundances to varying external conditions necessarily lead to the zonation of hepatic carbohydrate metabolism. To the best of our knowledge, this is the first kinetic tissue model which takes into account in a semi-mechanistic way all relevant levels of enzyme regulation
Bioenergetic mechanisms of seizure control
Epilepsy is characterized by the regular occurrence of seizures, which follow a stereotypical sequence of alterations in the electroencephalogram. Seizures are typically a self limiting phenomenon, concluding finally in the cessation of hypersynchronous activity and followed by a state of decreased neuronal excitability which might underlie the cognitive and psychological symptoms the patients experience in the wake of seizures. Many efforts have been devoted to understand how seizures spontaneously stop in hope to exploit this knowledge in anticonvulsant or neuroprotective therapies. Besides the alterations in ion-channels, transmitters and neuromodulators, the successive build up of disturbances in energy metabolism have been suggested as a mechanism for seizure termination. Energy metabolism and substrate supply of the brain are tightly regulated by different mechanisms called neurometabolic and neurovascular coupling. Here we summarize the current knowledge whether these mechanisms are sufficient to cover the energy demand of hypersynchronous activity and whether a mismatch between energy need and supply could contribute to seizure control
Computer Simulations Suggest a Key Role of Membranous Nanodomains in Biliary Lipid Secretion
The bile fluid contains various lipids that are secreted at the canalicular
membrane of hepatocytes. As the secretion mechanism is still a matter of
debate and a direct experimental observation of the secretion process is not
possible so far, we used a mathematical model to simulate the extraction of
the major bile lipids cholesterol, phosphatidylcholine and sphingomyelin from
the outer leaflet of the canalicular membrane. Lipid diffusion was modeled as
random movement on a triangular lattice governed by next-neighbor interaction
energies. Phase separation in liquid-ordered and liquid-disordered domains was
modeled by assigning two alternative ordering states to each lipid species and
minimization of next-neighbor ordering energies. Parameterization of the model
was performed such that experimentally determined diffusion rates and phases
in ternary lipid mixtures of model membranes were correctly recapitulated. The
model describes the spontaneous formation of nanodomains in the external
leaflet of the canalicular membrane in a time window between 0.1 ms to 10 ms
at varying lipid proportions. The extraction of lipid patches from the bile
salt soluble nanodomain into the bile reproduced observed biliary phospholipid
compositions for a physiologi-cal membrane composition. Comparing the outcome
of model simulations with available experi-mental observations clearly favors
the extraction of tiny membrane patches composed of about 100–400 lipids as
the likely mechanism of biliary lipid secretion
The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling
Background Adaptation of the cellular metabolism to varying external
conditions is brought about by regulated changes in the activity of enzymes
and transporters. Hormone-dependent reversible enzyme phosphorylation and
concentration changes of reactants and allosteric effectors are the major
types of rapid kinetic enzyme regulation, whereas on longer time scales
changes in protein abundance may also become operative. Here, we used a
comprehensive mathematical model of the hepatic glucose metabolism of rat
hepatocytes to decipher the relative importance of different regulatory modes
and their mutual interdependencies in the hepatic control of plasma glucose
homeostasis. Results Model simulations reveal significant differences in the
capability of liver metabolism to counteract variations of plasma glucose in
different physiological settings (starvation, ad libitum nutrient supply,
diabetes). Changes in enzyme abundances adjust the metabolic output to the
anticipated physiological demand but may turn into a regulatory disadvantage
if sudden unexpected changes of the external conditions occur. Allosteric and
hormonal control of enzyme activities allow the liver to assume a broad range
of metabolic states and may even fully reverse flux changes resulting from
changes of enzyme abundances alone. Metabolic control analysis reveals that
control of the hepatic glucose metabolism is mainly exerted by enzymes alone,
which are differently controlled by alterations in enzyme abundance,
reversible phosphorylation, and allosteric effects. Conclusion In hepatic
glucose metabolism, regulation of enzyme activities by changes of reactants,
allosteric effects, and reversible phosphorylation is equally important as
changes in protein abundance of key regulatory enzymes
Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced α
Reduced activity of brain α-ketoglutarate dehydrogenase complex (KGDHC) occurs in a number of neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. In order to quantify the relation between diminished KGDHC activity and the mitochondrial ATP generation, redox state, transmembrane potential, and generation of reactive oxygen species (ROS) by the respiratory chain (RC), we developed a detailed kinetic model. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. By contrast, progressive inhibition of the enzyme aconitase had only little impact on these mitochondrial parameters. As KGDHC is susceptible to ROS-dependent inactivation, we also investigated the reduction state of those sites of the RC proposed to be involved in ROS production. The reduction state of all sites except one decreased with increasing degree of KGDHC inhibition suggesting an ROS-reducing effect of KGDHC inhibition. Our model underpins the important role of reduced KGDHC activity in the energetic breakdown of neuronal cells during development of neurodegenerative diseases
A Conceptual Mathematical Model of the Dynamic Self-Organisation of Distinct Cellular Organelles
Formation, degradation and renewal of cellular organelles is a dynamic process based on permanent budding, fusion and inter-organelle traffic of vesicles. These processes include many regulatory proteins such as SNAREs, Rabs and coats. Given this complex machinery, a controversially debated issue is the definition of a minimal set of generic mechanisms necessary to enable the self-organization of organelles differing in number, size and chemical composition. We present a conceptual mathematical model of dynamic organelle formation based on interacting vesicles which carry different types of fusogenic proteins (FP) playing the role of characteristic marker proteins. Our simulations (ODEs) show that a de novo formation of non-identical organelles, each accumulating a different type of FP, requires a certain degree of disproportionation of FPs during budding. More importantly however, the fusion kinetics must indispensably exhibit positive cooperativity among these FPs, particularly for the formation of larger organelles. We compared different types of cooperativity: sequential alignment of corresponding FPs on opposite vesicle/organelles during fusion and pre-formation of FP-aggregates (equivalent, e.g., to SNARE clusters) prior to fusion described by Hill kinetics. This showed that the average organelle size in the system is much more sensitive to the disproportionation strength of FPs during budding if the vesicular transport system gets along with a fusion mechanism based on sequential alignments of FPs. Therefore, pre-formation of FP aggregates within the membranes prior to fusion introduce robustness with respect to organelle size. Our findings provide a plausible explanation for the evolution of a relatively large number of molecules to confer specificity on the fusion machinery compared to the relatively small number involved in the budding process. Moreover, we could speculate that a specific cooperativity which may be described by Hill kinetics (aggregates or Rab/SNARE complex formation) is suitable if maturation/identity switching of organelles play a role (bistability)
Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment
Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated β-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC
Functional Consequences of Metabolic Zonation in Murine Livers: Insights for an Old Story
Background and Aims:
Zone-dependent differences in expression of metabolic enzymes along the portocentral axis of the acinus are a long-known feature of liver metabolism. A prominent example is the preferential localization of the enzyme, glutamine synthetase, in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid, glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and, much more important, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far.
Approach and Results:
We addressed this problem by establishing a method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone-specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1).
Conclusions:
The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids, and detoxification
On the relationship between metabolic capacities and in vivo viscoelastic properties of the liver
The liver is the central metabolic organ. It constantly adapts its metabolic capacity to current physiological requirements. However, the relationship between tissue structure and hepatic function is incompletely understood; this results in a lack of diagnostic markers in medical imaging that can provide information about the liver's metabolic capacity. Therefore, using normal rabbit livers, we combined magnetic resonance elastography (MRE) with proteomics-based kinetic modeling of central liver metabolism to investigate the potential role of MRE for predicting the liver's metabolic function in vivo. Nineteen New Zealand white rabbits were investigated by multifrequency MRE and positron emission tomography (PET). This yielded maps of shear wave speed (SWS), penetration rate (PR) and standardized uptake value (SUV). Proteomic analysis was performed after the scans. Hepatic metabolic functions were assessed on the basis of the HEPATOKIN1 model in combination with a model of hepatic lipid-droplet metabolism using liquid chromatography-mass spectrometry. Our results showed marked differences between individual livers in both metabolic functions and stiffness properties, though not in SUV. When livers were divided into 'stiff' and 'soft' subgroups (cutoff SWS = 1.6 m/s), stiff livers showed a lower capacity for triacylglycerol storage, while at the same time showing an increased capacity for gluconeogenesis and cholesterol synthesis. Furthermore, SWS was correlated with gluconeogenesis and PR with urea production and glutamine exchange. In conclusion, our study indicates a close relationship between the viscoelastic properties of the liver and metabolic function. This could be used in future studies to predict non-invasively the functional reserve capacity of the liver in patients
Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy
During pregnancy, the body's hyperestrogenic state alters hepatic metabolism and synthesis. While biochemical changes related to liver function during normal pregnancy are well understood, pregnancy-associated alterations in biophysical properties of the liver remain elusive. In this study, we investigated 26 ex vivo fresh liver specimens harvested from pregnant and non-pregnant rats by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) in a 0.5-Tesla compact magnetic resonance imaging (MRI) scanner. Water diffusivity and viscoelastic parameters were compared with histological data and blood markers. We found livers from pregnant rats to have (i) significantly enlarged hepatocytes (26 ± 15%, p < 0.001), (ii) increased liver stiffness (12 ± 15%, p = 0.012), (iii) decreased viscosity (-23 ± 14%, p < 0.001), and (iv) increased water diffusivity (12 ± 11%, p < 0.001). In conclusion, increased stiffness and reduced viscosity of the liver during pregnancy are mainly attributable to hepatocyte enlargement. Hypertrophy of liver cells imposes fewer restrictions on intracellular water mobility, resulting in a higher hepatic water diffusion coefficient. Collectively, MRE and DWI have the potential to inform on structural liver changes associated with pregnancy in a clinical context
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