Characterization of Lipid and Lipid Droplet Metabolism in Human HCC
Nikolaus Berndt,
Johannes Eckstein,
Niklas Heucke,
Robert Gajowski,
Martin Stockmann,
David Meierhofer,
Hermann-Georg Holzhütter
Affiliations
Nikolaus Berndt
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
Johannes Eckstein
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
Niklas Heucke
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
Robert Gajowski
Max Planck Institute of Molecular Genetics, Mass Spectroscopy Facility, Ihnestraße 63–73, 14195 Berlin, Germany
Martin Stockmann
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
David Meierhofer
Max Planck Institute of Molecular Genetics, Mass Spectroscopy Facility, Ihnestraße 63–73, 14195 Berlin, Germany
Hermann-Georg Holzhütter
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
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.
