The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability; however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.

中文翻译：

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抑制肝脏脂肪生成可通过增加抗氧化剂防御能力并促进细胞存活来增强肝脏肿瘤发生。

从头脂肪形成的代谢途径在人肝肿瘤中经常上调，其上调与不良预后相关。阻断培养的肝癌细胞中的脂肪生成足以降低细胞活力。但是，尚不清楚在体内阻断脂肪生成是否可以预防肝肿瘤的发生。在这里，我们通过肝脏特异性的乙酰辅酶A羧化酶（ACC）基因敲除来抑制小鼠的肝脏脂肪生成，并用肝细胞致癌物二乙基亚硝胺（DEN）治疗小鼠。出乎意料的是，与对照组相比，缺乏肝脏脂肪生成的小鼠的肿瘤发生率和多重性增加了两倍。缺乏ACC的肝脏的代谢组学分析表明，抗氧化剂（包括NADPH）和谷胱甘肽的减少显着增加。重要的，用谷胱甘肽前体补充原代野生型肝细胞可将DEN治疗后的细胞存活率提高到与ACC缺乏型原代肝细胞无法区分的水平。这项研究表明，脂肪生成对于用DEN处理的小鼠的肝肿瘤发生是必不可少的，并且确定了ACC酶在氧化还原调节和细胞存活中的重要作用。