编码 β-连环蛋白的 CTNNB1 基因的激活突变是肝细胞癌 (HCC) 中最常见的致癌改变之一。 CTNNB1 突变的 HCC 中会发生脂质代谢的深刻改变，包括脂肪酸氧化和磷脂组转化的增加，但尚不清楚是什么机制引起这些变化。我们采用非靶向脂质组学和靶向同位素示踪来测量表达突变型 β-连环蛋白的诱导型人肝细胞系以及具有激活的 β-连环蛋白驱动的 HCC 的转基因斑马鱼中的磷脂合成活性。在这两种模型中，激活的β-连环蛋白表达与脂质组的巨大变化相关，包括酰基肉碱和神经酰胺的保守增加以及甘油三酯的减少。人体细胞中的脂质同位素示踪分析显示，通过胆碱掺入测定，磷脂酰胆碱 (PC) 生成率降低。我们开发了斑马鱼肿瘤的脂质同位素示踪分析，并观察到 ​​CDP-胆碱和 PEMT 途径导致磷脂酰胆碱合成减少。观察到的 β-连环蛋白驱动的 HCC 磷脂组的变化表明，斑马鱼可以重现 HCC 脂质代谢的保守特征，并可作为识别未来 HCC 特异性脂质代谢目标的模型。版权所有 © 2024。由 Elsevier B.V. 出版。

Activating mutations in the CTNNB1 gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with CTNNB1 mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC. In both models, activated β-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid isotope tracing analysis in human cells revealed a reduction in phosphatidylcholine (PC) production rates as assayed by choline incorporation. We developed lipid isotope tracing analysis for zebrafish tumors and observed reductions in phosphatidylcholine synthesis by both the CDP-choline and PEMT pathways. The observed changes in the β-catenin-driven HCC phospholipidome suggest that zebrafish can recapitulate conserved features of HCC lipid metabolism and may serve as a model for identifying future HCC-specific lipid metabolic targets.Copyright © 2024. Published by Elsevier B.V.