Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease.

中文翻译：

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锌指蛋白Zbtb20对肝脏脂肪生成的调节。

肝新生脂肪形成（DNL）将碳水化合物转化为甘油三酸酯，并且已知会影响全身性脂质的稳态。在这里，我们证明锌指蛋白Zbtb20是DNL所必需的。肝脏中缺乏Zbtb20的小鼠表现出低脂血症和肝脏甘油三酸酯水平降低，以及肝脂肪形成受损。在敲除小鼠的肝脏中，参与糖酵解和DNL的基因（包括两种ChREBP亚型）的表达降低。Zbtb20绑定并增强ChREBP-α启动子的活性，表明改变的代谢基因表达主要由ChREBP驱动。此外，ChREBP-β的过表达在很大程度上恢复了参与葡萄糖和脂质代谢的基因的肝表达，并增加了基因敲除小鼠的血浆和肝甘油三酯水平。最后，我们显示Zbtb20消融保护免受饮食诱导的肝脂肪变性并改善肝胰岛素抵抗。我们建议Z​​BTB20是肝脂肪生成的重要调节剂，并且可能是治疗脂肪肝疾病的治疗靶标。