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Author: Martin Stockmann3
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

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

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