Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
Laboratory of Cell Biochemistry and Molecular Biology, NIDDK, NIH, Bethesda, Maryland, USA.
Hepatol Commun. 2023 Nov 6;7(11). doi: 10.1097/HC9.0000000000000283. eCollection 2023 Nov 1.
O-GlcNAcylation is a post-translational modification catalyzed by the enzyme O-GlcNAc transferase, which transfers a single N-acetylglucosamine sugar from UDP-GlcNAc to the protein on serine and threonine residues on proteins. Another enzyme, O-GlcNAcase (OGA), removes this modification. O-GlcNAcylation plays an important role in pathophysiology. Here, we report that O-GlcNAcylation is essential for hepatocyte differentiation, and chronic loss results in fibrosis and HCC.
Single-cell RNA-sequencing (RNA-seq) was used to investigate hepatocyte differentiation in hepatocyte-specific O-GlcNAc transferase-knockout (OGT-KO) mice with decreased hepatic O-GlcNAcylation and in O-GlcNAcase-KO mice with increased O-GlcNAcylation in hepatocytes. Patients HCC samples and the diethylnitrosamine-induced HCC model were used to investigate the effect of modulation of O-GlcNAcylation on the development of liver cancer.
Loss of hepatic O-GlcNAcylation resulted in disruption of liver zonation. Periportal hepatocytes were the most affected by loss of differentiation, characterized by dysregulation of glycogen storage and glucose production. O-GlcNAc transferase-KO mice exacerbated diethylnitrosamine-induced HCC development with increased inflammation, fibrosis, and YAP signaling. Consistently, O-GlcNAcase -KO mice with increased hepatic O-GlcNAcylation inhibited diethylnitrosamine-induced HCC. A progressive loss of O-GlcNAcylation was observed in patients with HCC.
Our study shows that O-GlcNAcylation is a critical regulator of hepatic differentiation, and loss of O-GlcNAcylation promotes hepatocarcinogenesis. These data highlight increasing O-GlcNAcylation as a potential therapy in chronic liver diseases, including HCC.
O-糖基化是一种由酶 O-GlcNAc 转移酶催化的翻译后修饰，该酶将 UDP-GlcNAc 上的单个 N-乙酰葡萄糖胺糖转移到蛋白质上丝氨酸和苏氨酸残基上。另一种酶，O-GlcNAcase（OGA），去除这种修饰。O-糖基化在病理生理学中起着重要作用。在这里，我们报告 O-糖基化对于肝细胞分化至关重要，慢性缺失会导致纤维化和 HCC。
使用单细胞 RNA 测序（RNA-seq）来研究肝细胞特异性 O-GlcNAc 转移酶敲除（OGT-KO）小鼠中肝细胞 O-GlcNAc 化降低和 O-GlcNAcase 敲除（OGA-KO）小鼠中肝细胞 O-GlcNAc 化增加时的肝细胞分化。使用 HCC 患者样本和二乙基亚硝胺诱导的 HCC 模型来研究 O-GlcNAc 化的调节对肝癌发展的影响。
肝 O-GlcNAc 化的缺失导致肝脏分区的破坏。门脉周围的肝细胞受到分化缺失的影响最大，其特征是糖原储存和葡萄糖产生的失调。O-GlcNAc 转移酶 KO 小鼠加剧了二乙基亚硝胺诱导的 HCC 发展，伴有炎症、纤维化和 YAP 信号的增加。一致地，肝细胞 O-GlcNAc 化增加的 OGA-KO 小鼠抑制了二乙基亚硝胺诱导的 HCC。在 HCC 患者中观察到 O-GlcNAc 化的逐渐丧失。
我们的研究表明，O-GlcNAc 化是肝分化的关键调节因子，O-GlcNAc 化的缺失促进肝癌发生。这些数据突出了增加 O-GlcNAc 化作为慢性肝病（包括 HCC）的潜在治疗方法。
Zotero 插件
