Metabolomic Insights into HCF-1-dependent Regulation of Liver Homeostasis

Host cell factor-1 (HCF-1) is a conserved transcriptional and epigenetic coregulator known to influence hepatocyte proliferation, liver regeneration, and lipid metabolism. While its role in transcriptional control and chromatin dynamics has been explored, the metabolic consequences of HCF-1 loss remain incompletely understood.

To investigate the metabolic alterations triggered by hepatocyte-specific HCF-1 loss in murine liver and their potential relevance to metabolic-associated fatty liver disease (MAFLD).

Using Alb-Cre-ERT2 ^tg ; Hcfc1 ^hepKO/Y mice, we performed targeted metabolomic profiling of liver tissues across a seven-day time course post-knockout using the AbsoluteIDQ® p180 platform (Biocrates Life Science AG). Global changes in metabolic signatures were examined in conjunction with histological, biochemical, ultrastructural, and protein-level assessments of hepatic pathology and compared with published human metabolomic datasets.

HCF-1 deficiency caused rapid and progressive metabolic rewiring, characterized by elevated bile acids, phosphatidylcholines, lysophosphatidylcholines, and acylcarnitines, with concurrent depletion of sphingolipids. Key dysregulated pathways included β-oxidation, mitochondrial energy metabolism, unsaturated fatty acid biosynthesis, and peroxisomal lipid processing. Electron microscopy revealed marked mitochondrial structural abnormalities, accompanied by impaired mitochondrial function and a significant reduction in PGC1α protein levels, a key regulator of mitochondrial biogenesis and oxidative metabolism. Temporal and integrative analysis revealed early bile acid and amino acid imbalance, advancing to severe lipid dysregulation, key effects that resemble aspects of the MAFLD-to-metabolic-associated steatohepatitis (MASH) transition. Comparative pathway mapping demonstrated substantial overlap between murine and human metabolic alterations, suggesting convergence on common metabolic pathways and supporting the translational relevance of the findings.

Our results uncover a crucial role for HCF-1 in maintaining hepatic metabolic homeostasis. By integrating metabolomic insights with known epigenetic and transcriptional functions, this study strengthens the view of HCF-1 as a multifaceted regulator whose loss disrupts core hepatic processes associated with MAFLD progression.