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10 Publications visible to you, out of a total of 10
Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis.

Abstract (Expand)

Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife … increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by (1)H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.

Authors: S. Schreyer, N. Berndt, J. Eckstein, M. Mulleder, S. Hemmati-Sadeghi, C. Klein, B. Abuelnor, A. Panzel, D. Meierhofer, J. Spranger, B. Steiner, S. Brachs

Date Published: 16th Apr 2021

Publication Type: Journal

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment.

Abstract (Expand)

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 beta-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.

Authors: N. Berndt, J. Eckstein, Niklas Heucke, T. Wuensch, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 8th Oct 2020

Publication Type: Journal

Functional consequences of metabolic zonation in murine livers: New insights for an old story.

Abstract (Expand)

BACKGROUND & AIMS: Zone-dependent differences in the expression of metabolic enzymes along the porto-central 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 importantly, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. APPROACH & RESULTS: We addressed this problem by establishing a new 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). CONCLUSION: The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids and detoxification.

Authors: N. Berndt, E. Kolbe, R. Gajowski, J. Eckstein, F. Ott, D. Meierhofer, H. G. Holzhutter, M. Matz-Soja

Date Published: 14th Apr 2020

Publication Type: Not specified

Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming.

Abstract (Expand)

Protein modification with ISG15 (ISGylation) represents a major type I IFN-induced antimicrobial system. Common mechanisms of action and species-specific aspects of ISGylation, however, are still ill … defined and controversial. We used a multiphasic coxsackievirus B3 (CV) infection model with a first wave resulting in hepatic injury of the liver, followed by a second wave culminating in cardiac damage. This study shows that ISGylation sets nonhematopoietic cells into a resistant state, being indispensable for CV control, which is accomplished by synergistic activity of ISG15 on antiviral IFIT1/3 proteins. Concurrent with altered energy demands, ISG15 also adapts liver metabolism during infection. Shotgun proteomics, in combination with metabolic network modeling, revealed that ISG15 increases the oxidative capacity and promotes gluconeogenesis in liver cells. Cells lacking the activity of the ISG15-specific protease USP18 exhibit increased resistance to clinically relevant CV strains, therefore suggesting that stabilizing ISGylation by inhibiting USP18 could be exploited for CV-associated human pathologies.

Authors: M. Kespohl, C. Bredow, K. Klingel, M. Voss, A. Paeschke, M. Zickler, W. Poller, Z. Kaya, J. Eckstein, H. Fechner, J. Spranger, M. Fahling, E. K. Wirth, L. Radoshevich, F. Thery, F. Impens, N. Berndt, K. P. Knobeloch, A. Beling

Date Published: 21st Mar 2020

Publication Type: Not specified

Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer

Abstract

Not specified

Authors: Nikolaus Berndt, Antje Egners, Guido Mastrobuoni, Olga Vvedenskaya, Athanassios Fragoulis, Aurélien Dugourd, Sascha Bulik, Matthias Pietzke, Chris Bielow, Rob van Gassel, Steven W. Olde Damink, Merve Erdem, Julio Saez-Rodriguez, Hermann-Georg Holzhütter, Stefan Kempa, Thorsten Cramer

Date Published: 10th Dec 2019

Publication Type: Not specified

Diagnostic performance of tomoelastography of the liver and spleen for staging hepatic fibrosis

Abstract

Not specified

Authors: Rolf Reiter, Heiko Tzschätzsch, Florian Schwahofer, Matthias Haas, Christian Bayerl, Marion Muche, Dieter Klatt, Shreyan Majumdar, Meltem Uyanik, Bernd Hamm, Jürgen Braun, Ingolf Sack, Patrick Asbach

Date Published: 11th Nov 2019

Publication Type: Not specified

Characterization of Lipid and Lipid Droplet Metabolism in Human HCC.

Abstract (Expand)

Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have … mainly focused on the glucose metabolism (Warburg effect), less attention has been paid to tumor-specific features of the lipid metabolism. Here, we applied a computational approach to analyze major pathways of fatty acid utilization in individual HCC. To this end, we used protein intensity profiles of eleven human HCCs to parameterize tumor-specific kinetic models of cellular lipid metabolism including formation, enlargement, and degradation of lipid droplets (LDs). Our analysis reveals significant inter-tumor differences in the lipid metabolism. The majority of HCCs show a reduced uptake of fatty acids and decreased rate of beta-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of beta-oxidation. Despite reduced fatty acid uptake in the majority of HCCs, the content of triacylglycerol is significantly enlarged compared to the tumor-adjacent tissue. This is due to tumor-specific expression profiles of regulatory proteins decorating the surface of LDs and controlling their turnover. Our simulations suggest that HCCs characterized by a very high content of triglycerides comprise regulatory peculiarities that render them susceptible to selective drug targeting without affecting healthy tissue.

Authors: N. Berndt, J. Eckstein, Niklas Heucke, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 27th May 2019

Publication Type: Not specified

HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology.

Abstract (Expand)

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, … medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

Authors: N. Berndt, S. Bulik, I. Wallach, T. Wunsch, M. Konig, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 21st Jun 2018

Publication Type: Not specified

The importance of membrane microdomains for bile salt-dependent biliary lipid secretion.

Abstract (Expand)

Alternative models explaining the biliary lipid secretion at the canalicular membrane of hepatocytes exist: successive lipid extraction by preformed bile salt micelles, or budding of membrane fragments … with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to form a rim to liquid disordered domain patches that then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates upon modulation of the membrane cholesterol (lack or overexpression of the cholesterol transporter Abcg5-Abcg8) and phosphatidylcholine (lack of Mdr2, also known as Abcb4) content. The model reveals a strong dependence of the biliary secretion rate on the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation.

Authors: J. Eckstein, H. G. Holzhutter, N. Berndt

Date Published: 1st Mar 2018

Publication Type: Not specified

A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism.

Abstract (Expand)

The capacity of the liver to convert the metabolic input received from the incoming portal and arterial blood into the metabolic output of the outgoing venous blood has three major determinants: The … intra-hepatic blood flow, the transport of metabolites between blood vessels (sinusoids) and hepatocytes and the metabolic capacity of hepatocytes. These determinants are not constant across the organ: Even in the normal organ, but much more pronounced in the fibrotic and cirrhotic liver, regional variability of the capillary blood pressure, tissue architecture and the expression level of metabolic enzymes (zonation) have been reported. Understanding how this variability may affect the regional metabolic capacity of the liver is important for the interpretation of functional liver tests and planning of pharmacological and surgical interventions. Here we present a mathematical model of the sinusoidal tissue unit (STU) that is composed of a single sinusoid surrounded by the space of Disse and a monolayer of hepatocytes. The total metabolic output of the liver (arterio-venous glucose difference) is obtained by integration across the metabolic output of a representative number of STUs. Application of the model to the hepatic glucose metabolism provided the following insights: (i) At portal glucose concentrations between 6-8 mM, an intra-sinusoidal glucose cycle may occur which is constituted by glucose producing periportal hepatocytes and glucose consuming pericentral hepatocytes, (ii) Regional variability of hepatic blood flow is higher than the corresponding regional variability of the metabolic output, (iii) a spatially resolved metabolic functiogram of the liver is constructed. Variations of tissue parameters are equally important as variations of enzyme activities for the control of the arterio-venous glucose difference.

Authors: N. Berndt, M. S. Horger, S. Bulik, H. G. Holzhutter

Date Published: 16th Feb 2018

Publication Type: Not specified

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