PDF(Pubmed)
Abstract：
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver-related morbidity and mortality. Though high fructose intake is acknowledged as a metabolic hazard, its role in the etiology of MASLD requires further clarification. Here, we demonstrated that high dietary fructose drives MASLD development and promotes MASLD progression in mice, and identified Usp2 as a fructose-responsive gene in the liver. Elevated USP2 levels were detected in the hepatocytes of MASLD mice; a similar increase was observed following fructose exposure in primary hepatocytes and mouse AML12 cells. Notably, hepatocytes overexpressing USP2 presented with exaggerated lipid accumulation and metabolic inflammation when exposed to fructose. Conversely, USP2 knockdown mitigated these fructose-induced changes. Furthermore, USP2 was found to activate the C/EBPα/11β-HSD1 signaling, which further impacted the equilibrium of cortisol and cortisone in the circulation of mice. Collectively, our findings revealed the role of dietary fructose in MASLD pathogenesis and identified the USP2-mediated C/EBPα/ 11β-HSD1 signaling as a potential target for the management of MASLD.
摘要：
代谢功能障碍相关的脂肪变性肝病（MASLD）是慢性肝脏相关发病率和死亡率的最常见原因。虽然高果糖摄入被认为是一种代谢危害，其在MASLD病因中的作用需要进一步阐明。这里,我们证明，高膳食果糖驱动小鼠的MASLD发育并促进MASLD进展，并将Usp2鉴定为肝脏中的果糖反应基因。在MASLD小鼠的肝细胞中检测到升高的USP2水平;在原代肝细胞和小鼠AML12细胞中的果糖暴露后观察到类似的增加。值得注意的是,当暴露于果糖时，过表达USP2的肝细胞呈现过度的脂质积累和代谢炎症。相反，USP2敲低减轻了这些果糖诱导的变化。此外，发现USP2激活C/EBPα/11β-HSD1信号,这进一步影响了小鼠循环中皮质醇和可的松的平衡。总的来说，我们的研究结果揭示了膳食果糖在MASLD发病机制中的作用,并确定了USP2介导的C/EBPα/11β-HSD1信号传导作为MASLD治疗的潜在靶点.
