Zhang Lei, Han Cuijuan, Shrestha Man Mohan, Le Jiamei, Berger Wilhelm K, Huang Yiheng, Desrouleaux Reina, Wang Eric, Nagy Laszlo, Yang Xiaoyong
Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
Hepatology. 2025 Jun 30. doi: 10.1097/HEP.0000000000001445.
Metabolic dysfunction-associated fatty liver disease (MASLD) encompasses a spectrum of liver pathologies ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. The mechanisms governing disease progression, particularly the communication between hepatocytes and non-parenchymal cells, remain poorly understood. In this study, we demonstrate a novel paracrine factor through which O‑GlcNAc transferase (OGT) regulates intercellular crosstalk between hepatocytes and immune cells in MASH development.
OGT and trefoil factor 2 (TFF2) expression were analyzed in human and mouse livers. The effects of the paracrine factor on inflammation and fibrogenesis were further evaluated in a 3D mouse liver spheroid model of MASH. The GalNAc-modified siRNA targeting the paracrine factor was applied in Gubra-Amylin NASH (GAN) diet-fed mice to determine its therapeutic potential in preventing the MASH progression. Decreased OGT expression during MASLD promotes TFF2 transcription and secretion via forkhead box protein A2 (FOXA2) modulation. In 3D mouse liver spheroids, TFF2 exacerbates MASH-related pathologies. Mechanistically, TFF2 enhances hepatic CD4+ T cell proliferation and Th1/Th17 differentiation through CXC motif chemokine receptor 4 (CXCR4)-signal transducer and activator of transcription 1/3 (STAT1/3) signaling, cooperating with CXC motif chemokine ligand 12 (CXCL12) to amplify inflammation. Hepatocyte-specific Tff2 inhibition using GalNAc-modified siRNA in a diet-induced mouse model ameliorates MASH progression without affecting simple steatosis development.
These results identify an OGT-TFF2 axis that mediates the crosstalk between hepatocytes and CD4 T cells during MASH pathogenesis, revealing a potential therapeutic target for the treatment of chronic liver disease.
代谢功能障碍相关脂肪性肝病（MASLD）涵盖了一系列肝脏病变，从单纯性脂肪变性到伴有纤维化的代谢功能障碍相关脂肪性肝炎（MASH）。疾病进展的机制，尤其是肝细胞与非实质细胞之间的通讯，仍知之甚少。在本研究中，我们证明了一种新的旁分泌因子，通过它O-连接N-乙酰葡糖胺转移酶（OGT）在MASH发生发展过程中调节肝细胞与免疫细胞之间的细胞间串扰。
分析了人和小鼠肝脏中OGT和三叶因子2（TFF2）的表达。在MASH的三维小鼠肝脏球体模型中进一步评估了旁分泌因子对炎症和纤维化形成的影响。将靶向旁分泌因子的GalNAc修饰的小干扰RNA应用于给予古布拉-胰淀素非酒精性脂肪性肝炎（GAN）饮食的小鼠，以确定其在预防MASH进展方面的治疗潜力。MASLD期间OGT表达降低通过叉头框蛋白A2（FOXA2）调节促进TFF2转录和分泌。在三维小鼠肝脏球体中，TFF2加剧了与MASH相关的病理变化。机制上，TFF2通过CXC基序趋化因子受体4（CXCR4）-信号转导和转录激活因子1/3（STAT1/3）信号增强肝CD4+T细胞增殖和Th1/Th17分化，与CXC基序趋化因子配体12（CXCL12）协同放大炎症。在饮食诱导的小鼠模型中，使用GalNAc修饰的小干扰RNA抑制肝细胞特异性Tff2可改善MASH进展，而不影响单纯性脂肪变性的发展。
这些结果确定了一个OGT-TFF2轴，该轴在MASH发病机制中介导肝细胞与CD4 T细胞之间的串扰，揭示了慢性肝病治疗的潜在治疗靶点。
