Chromatin remodeling in pericentral hepatocytes modulates MASH through CYP450 activity

Area of Science:

• Hepatology and metabolic disease research.
• Epigenetics and chromatin regulation in liver function.
• Cell-specific mechanisms in liver zonation.

Background:

• Lgr5+ hepatocytes are key to liver metabolism, but their role in metabolic stress is unclear.
• Chronic liver diseases like MASLD/MASH involve widespread lipid accumulation.
• Understanding zone-specific hepatocyte responses is vital for metabolic liver disease research.

Purpose of the Study:

• To investigate the role of DPF2 in Lgr5+ hepatocytes in maintaining liver metabolic homeostasis.
• To elucidate the mechanisms by which DPF2 regulates all-trans retinoic acid (atRA) and AMPK signaling.
• To explore the therapeutic potential of targeting the CYP2-atRA-AMPK axis in MASLD and MASH.

Main Methods:

• Induction of MASLD/MASH in mice using specific diets.
• Multi-modal analyses including scRNA-seq, spatial transcriptomics, ATAC-seq, CUT&Tag, and CUT&RUN.
• Functional interventions such as pharmacological atRA supplementation and CYP2 inhibition.

Main Results:

• Dpf2 deletion in Lgr5+ hepatocytes led to hepatic lipid accumulation and disrupted metabolic homeostasis.
• DPF2 loss increased CYP2 enzyme expression, causing excessive atRA catabolism and reduced AMPK phosphorylation.
• Restoring atRA levels ameliorated MASLD severity, demonstrating a non-cell-autonomous protective mechanism.

Conclusions:

• DPF2 in Lgr5+ hepatocytes is a critical regulator of hepatic metabolism via the CYP2-atRA-AMPK axis.
• This study reveals zone-specific metabolic control mechanisms in the liver.
• atRA homeostasis is identified as a potential therapeutic target for MASLD and MASH.