Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival.
Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival.
复制标题
DOI：
10.1038/ncomms14689
复制
发表时间：
2017-03-14
影响因子：
16.6
通讯作者：
Hoehn KL
中科院分区：
文献类型：
--
作者：
Nelson ME;Lahiri S;Chow JD;Byrne FL;Hargett SR;Breen DS;Olzomer EM;Wu LE;Cooney GJ;Turner N;James DE;Slack-Davis JK;Lackner C;Caldwell SH;Hoehn KL
从头脂肪生成的代谢途径在人类肝脏肿瘤中经常上调，并且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;然而，尚不清楚体内阻断脂肪生成是否可以预防肝肿瘤发生。在此，我们通过肝脏特异性敲除乙酰辅酶A羧化酶（ACC）基因来抑制小鼠肝脏脂肪生成，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病率和多样性增加了两倍。ACC缺陷肝脏的代谢组学分析确定了抗氧化剂（包括NADPH和还原型谷胱甘肽）的显着增加。重要的是，用谷胱甘肽前体补充原代野生型肝细胞可提高DEN治疗后的细胞存活率，使其与ACC缺陷原代肝细胞无法区分。这项研究表明，脂肪生成与DEN治疗的小鼠的肝脏肿瘤发生有关，并确定了ACC酶在氧化还原调节和细胞存活中的重要作用。脂肪生成途径通常在肝肿瘤中上调，并被视为治疗靶点。在这里，作者表明，相反，通过敲除乙酰辅酶A羧化酶基因来阻断脂肪生成会导致与抗氧化防御增加相关的肝脏肿瘤发生的易感性增加。
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. The lipogenic pathway is often upregulated in liver tumours and regarded as a therapeutic target. Here, the authors show instead that blocking lipogenesis via knockout of acetyl-CoA carboxylase genes results in increased susceptibility to liver tumorigenesis associated with an increased antioxidant defence.