Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, China.
Int J Biol Sci. 2024 Jun 17;20(9):3480-3496. doi: 10.7150/ijbs.97309. eCollection 2024.
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 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.
代谢相关脂肪性肝病（MASLD）是导致慢性肝相关发病率和死亡率的最常见原因。尽管高果糖摄入已被认为是一种代谢危害，但它在 MASLD 病因学中的作用仍需进一步阐明。在这里，我们证明了高果糖饮食会导致 MASLD 的发生和发展，并促进了小鼠 MASLD 的进展，同时鉴定出 USP2 是肝脏中对果糖有反应的基因。在 MASLD 小鼠的肝细胞中检测到 USP2 水平升高；在原代肝细胞和小鼠 AML12 细胞中，果糖暴露后也观察到类似的增加。值得注意的是，当果糖暴露时，过表达 USP2 的肝细胞表现出脂质积累和代谢炎症的加剧。相反，USP2 的敲低减轻了这些果糖诱导的变化。此外，发现 USP2 激活了 C/EBPα/11β-HSD1 信号通路，这进一步影响了小鼠循环中皮质醇和可的松的平衡。综上所述，我们的研究结果揭示了饮食果糖在 MASLD 发病机制中的作用，并确定了 USP2 介导的 C/EBPα/11β-HSD1 信号通路是 MASLD 管理的潜在靶点。
