Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom.
Biomolecular MedicineDivision of Systems MedicineDepartment of Metabolism, Digestion and ReproductionImperial College LondonLondonUnited Kingdom.
Hepatology. 2021 Mar;73(3):1028-1044. doi: 10.1002/hep.31391. Epub 2020 Nov 3.
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.
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.
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.
当肝实质细胞在代偿性再生和肝细胞癌（HCC）中被诱导增殖时，它们会经历深刻的代谢重编程。然而，这些过程的代谢调控尚不完全清楚。为了捕捉增殖性肝实质细胞的代谢特征，我们应用最先进的系统生物学方法，研究了肝再生的模型、药理学和遗传学激活的细胞增殖以及 HCC。
我们将代谢组学、脂质组学和转录组学相结合，将增殖性肝实质细胞的脂质组变化与包括脂肪生成、脂肪酸去饱和和磷脂酰胆碱（PC）生成在内的代谢途径的改变联系起来。我们在人类 HCC 中证实了这种改变的脂质特征，并显示出单不饱和 PC 与细胞增殖和肝发生的标志之间存在正相关关系。
总的来说，我们证明了当肝实质细胞向增殖状态转变时，特定的脂质代谢途径会发生一致的改变。这些代表了开发治疗策略和 HCC 预后生物标志物的潜在靶点。
