2026
Journal of Clinical and Experimental Hepatology 2026 Jul 2. doi: 10.1016/j.jceh.2026.103602
Metabolomic insights into HCF-1-dependent regulation of liver homeostasis
Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India Department of Computational Biology, Indraprastha Institute of Information Technology (IIITD), Okhla Industrial Estate, Phase III, New Delhi, 110020, India Centre of Excellence for Healthcare, Indraprastha Institute of Information Technology (IIITD), Okhla Industrial Estate, Phase III, New Delhi, 110020, India Centre for Integrative Genomics (CIG), Génopode, University of Lausanne, Lausanne 1015, Switzerland
Service type: Knockout mice
Abstract
Background Host Cell Factor 1 (HCF-1) is a conserved transcriptional and epigenetic co-regulator 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. Objective 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). Methods Using Alb-Cre-ERT2tg; Hcfc1hepKO/Y mice, we performed targeted metabolomic profiling of liver tissues across a 7-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. Results 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-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. Conclusion 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.
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