Kapuria Vaibhav, Herr Winship, Minocha Shilpi
Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.
Amity Institute of Biotechnology, Amity University Haryana, Gurgaon, 122413, Haryana, India.
Sci Rep. 2025 Aug 3;15(1):28328. doi: 10.1038/s41598-025-11813-1.
Host cell factor-1 (HCF-1) is a transcriptional coregulator essential for maintaining liver function and cellular metabolism. O-linked N-acetylglucosamine transferase (OGT) is a key nutrient-sensing enzyme that catalyzes protein O-GlcNAcylation, a critical post-translational modification regulating metabolic pathways. This study investigates the role of hepatocyte-specific depletion of HCF-1 in regulating OGT stability, activity, and cellular localization in hepatocytes. Using a transgenic mouse model with hepatocyte-specific HCF-1 deletion, we assessed the impact of HCF-1 loss on OGT expression and O-GlcNAcylation activity. OGT protein levels, mRNA expression, and cellular localization were evaluated using molecular and histological techniques. Comparisons were made with control mice and hepatocytes under nutrient-starved conditions. Hepatocyte-specific HCF-1 deletion led to progressive loss of HCF-1 protein and a concomitant decrease in OGT levels and global O-GlcNAcylation. Loss of HCF-1 did not alter OGT mRNA levels, suggesting post-translational regulation. Immunofluorescence revealed reduced nuclear OGT and O-GlcNAcylation, mimicking changes observed under fasting conditions. Isolated HCF-1-deficient hepatocytes showed impaired adhesion, further underscoring HCF-1's role in hepatocyte function. Notably, in heterozygous Hcfc1 females, HCF-1-negative hepatocytes displayed cytoplasmic O-GlcNAcylation, while HCF-1-positive cells maintained nuclear localization. HCF-1 is crucial for regulating OGT stability, activity, and nuclear localization in hepatocytes. These findings establish a mechanistic link between HCF-1 and OGT, highlighting their coordinated role in hepatic nutrient sensing and metabolic regulation.
宿主细胞因子-1（HCF-1）是维持肝功能和细胞代谢所必需的转录共调节因子。O-连接的N-乙酰葡糖胺转移酶（OGT）是一种关键的营养感应酶，可催化蛋白质O-糖基化，这是一种调节代谢途径的关键翻译后修饰。本研究探讨肝细胞特异性缺失HCF-1在调节肝细胞中OGT稳定性、活性和细胞定位方面的作用。使用具有肝细胞特异性HCF-1缺失的转基因小鼠模型，我们评估了HCF-1缺失对OGT表达和O-糖基化活性的影响。使用分子和组织学技术评估OGT蛋白水平、mRNA表达和细胞定位。并与对照小鼠和营养饥饿条件下的肝细胞进行比较。肝细胞特异性HCF-1缺失导致HCF-1蛋白逐渐丧失，同时OGT水平和整体O-糖基化降低。HCF-1的缺失并未改变OGT mRNA水平，提示存在翻译后调控。免疫荧光显示核内OGT和O-糖基化减少，类似于在禁食条件下观察到的变化。分离的HCF-1缺陷型肝细胞显示粘附受损，进一步强调了HCF-1在肝细胞功能中的作用。值得注意的是，在杂合子Hcfc1雌性小鼠中，HCF-1阴性肝细胞表现出细胞质O-糖基化，而HCF-1阳性细胞保持核定位。HCF-1对于调节肝细胞中OGT的稳定性、活性和核定位至关重要。这些发现建立了HCF-1与OGT之间的机制联系，突出了它们在肝脏营养感应和代谢调节中的协同作用。
