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Characterization of Lipid and Lipid Droplet Metabolism in Human HCC

1
Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biochemistry, Charitéplatz 1, 10117 Berlin, Germany
2
Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
3
Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Augustenburger Platz 1, 13353 Berlin, Germany
4
Max Planck Institute of Molecular Genetics, Mass Spectroscopy Facility, Ihnestraße 63–73, 14195 Berlin, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 512; https://doi.org/10.3390/cells8050512
Received: 9 May 2019 / Revised: 20 May 2019 / Accepted: 21 May 2019 / Published: 27 May 2019
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Abstract

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 β-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of β-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. View Full-Text
Keywords: tumor metabolism; lipid droplet metabolism; mathematical model; kinetic modeling; liver; hepatocellular carcinoma tumor metabolism; lipid droplet metabolism; mathematical model; kinetic modeling; liver; hepatocellular carcinoma
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Berndt, N.; Eckstein, J.; Heucke, N.; Gajowski, R.; Stockmann, M.; Meierhofer, D.; Holzhütter, H.-G. Characterization of Lipid and Lipid Droplet Metabolism in Human HCC. Cells 2019, 8, 512.

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