Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma.

Abstract

BACKGROUND AND AIMS: Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state-of-the-art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC. APPROACH AND RESULTS: Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis. CONCLUSIONS: Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.J.L.G., Z.H. and M.V. are funded by the Medical Research Council (MRC grant MC UP A90 1006 & MC PC 13030). J.L.G. and Z.H. are supported by the Imperial Biomedical Research Centre, NIHR. M.A., A.V-P., F.O., Q.M.A. and M.V. are members of the EPoS consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413. F.O. is supported by MRC program grants (MR/K0019494/1 and MR/R023026/1). J.L is supported by MRC PhD studentship and a CRUK program grant (C18342/A23390). M.V. and A.V-P. are supported by MRC MDU and MRC DMC (MC UU 12012/2). Q.M.A. received additional research support from The Liver Research Trust and is a Newcastle NIHR Biomedical Research Centre investigator. M.A., M.V., A.V-P. and J.L.G. received research support from the Evelyn Trust and the NIHR Cambridge Biomedical Research Centre (Gastroenterology Theme)