2025
Sci Rep. 2025 Aug 3;15(1):28328. doi: 10.1038/s41598-025-11813-1.
HCF-1 as a key modulator of OGT function and O-GlcNAcylation in the liver
Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland. Amity Institute of Biotechnology, Amity University Haryana, Gurgaon, 122413, Haryana, India. Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India. Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland. Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland. Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
Service type: Knockout mice
Abstract
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 Hcfc1hepKO/ + 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.
Keywords: O-GlcNAcylation; O‐linked N‐acetylglucosamine (O‐GlcNAc) transferase (OGT); Hepatocytes; Host cell factor-1; Liver; Nutrient sensing.
