Chromatin remodeling in pericentral hepatocytes modulates MASH through CYP450 activity

Lgr5⁺ hepatocytes constitute a specialized lineage central to nutrient and xenobiotic metabolism. In metabolic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH), lipid accumulation occurs throughout the liver; however, zone-specific hepatocyte responses to metabolic stress remain poorly understood. Here, we investigated the role of the SWI/SNF subunit DPF2 in Lgr5⁺ hepatocytes and its contribution to hepatic metabolic homeostasis and radiation induced liver damage (RILD).

Transgenic C57BL/6J mice were fed fructose-palmitate-cholesterol or choline-deficient amino acid-defined and high fat diets under pathogen-free conditions to induce MASLD/MASH. Multi-modal analyses - including single-cell RNA sequencing, spatial transcriptomics, ATAC sequencing, CUT&Tag, and CUT&RUN - were used to define the epigenetic and transcriptional regulation of cytochrome P450 family 2 subfamily (Cyp2) genes in Lgr5⁺ hepatocytes. Functional interventions included pharmacological all-trans retinoic acid (atRA) supplementation, CYP2 inhibition, and gene delivery via adeno-associated viruses or hydrodynamic tail vein injection.

Dpf2 deletion in Lgr5⁺ hepatocytes disrupted liver metabolic homeostasis, resulting in marked hepatic lipid accumulation and RILD. DPF2 loss increased chromatin accessibility and histone activation marks at Cyp2 promoters, driving CYP2 enzyme expression and excessive atRA catabolism. The resulting reduction in atRA decreased AMPK phosphorylation throughout the liver. Restoration of atRA rescued AMPK activity and ameliorated MASLD severity, highlighting a metabolite-mediated, non-cell-autonomous mechanism linking a small hepatocyte subset to whole-liver metabolic regulation.

DPF2 in Lgr5⁺ hepatocytes is a critical regulator of hepatic metabolism, acting via the CYP2-atRA-AMPK axis. These findings reveal the mechanistic basis for zone-specific metabolic control in the liver and identify atRA homeostasis as a potential therapeutic target for MASLD and MASH.

This study dissects chromatin regulation across spatially distinct hepatocyte populations and demonstrates that DPF2 activity within a rare Lgr5⁺ hepatocyte subset is sufficient to drive metabolic reprogramming and MASLD progression. These findings have important implications for both liver research and clinical practice, highlighting how liver-wide genetic manipulations or bulk omics analyses may obscure key disease-driving mechanisms confined to spatially restricted cell populations. From a translational perspective, our data suggest that targeting chromatin regulators or retinoid metabolic pathways may provide effective and safe therapeutic benefit; notably, systemic atRA administration can still confer robust protection or prevention at the whole-liver level. Although supported by rigorous mouse genetics, high-resolution transcriptomics, and validation in human liver tissues, clinical translation will require confirmation in larger human cohorts and carefully designed patient studies.