Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.

中文翻译：

---

肝脏 ChREBP 通过调节 L 型丙酮酸激酶防止果糖诱导的糖原性肝毒性

果糖摄入过多与代谢性疾病的发病机制密切相关。碳水化合物反应元件结合蛋白 (ChREBP) 是小鼠果糖耐受性必不可少的转录因子。然而，肝脏 ChREBP 在果糖代谢中的功能意义仍不清楚。在这里，我们表明肝脏 ChREBP 通过调节肝糖原代谢和 ATP 稳态来保护小鼠免受果糖诱导的肝毒性。ChREBP 的肝脏特异性消融不会影响果糖耐受性，而是在喂食高果糖饮食的小鼠中引起严重的转氨酶和肝肿大，伴有大量糖原过载，而在肝脏中未检测到明显的炎症、细胞死亡或纤维化。此外，在进食状态下，ChREBP 缺乏会显着降低肝脏 ATP 含量，果糖喂养使这一点变得更加明显。从机制上讲，在没有肝脏 ChREBP 的情况下，6-磷酸葡萄糖 (G6P)（一种糖原合成酶的变构激活剂）的肝脏含量显着增加，而禁食诱导的糖原分解并未受到影响。此外，LPK（糖酵解中的 ChREBP 靶基因）的肝脏过表达可以有效地挽救糖原过载和 ATP 减少，并减轻果糖诱导的 ChREBP 缺陷小鼠的肝毒性。总之，我们的研究结果确立了肝脏 ChREBP 在应对肝脏果糖应激和通过调节 LPK 防止肝毒性方面的关键作用。而禁食引起的糖原分解没有受到影响。此外，LPK（糖酵解中的 ChREBP 靶基因）的肝脏过表达可以有效地挽救糖原过载和 ATP 减少，并减轻果糖诱导的 ChREBP 缺陷小鼠的肝毒性。总之，我们的研究结果确立了肝脏 ChREBP 在应对肝脏果糖应激和通过调节 LPK 防止肝毒性方面的关键作用。而禁食引起的糖原分解没有受到影响。此外，LPK（糖酵解中的 ChREBP 靶基因）的肝脏过表达可以有效地挽救糖原过载和 ATP 减少，并减轻果糖诱导的 ChREBP 缺陷小鼠的肝毒性。总之，我们的研究结果确立了肝脏 ChREBP 在应对肝脏果糖应激和通过调节 LPK 防止肝毒性方面的关键作用。