Abstract

The liver is an exclusive organ with tremendous regenerative capacity. Liver metabolic functions exhibit spatial heterogeneity, reflecting liver zonation. The mechanisms controlling the proliferation of hepatocytes and the accompanying matrix reconstruction during regeneration have been well explored, but the recovery potential of differentiated metabolic functions and zonation after liver injury remains unclear. We employed a mouse model of carbon tetrachloride (CCl4) induced-acute liver injury with clodronate-induced macrophage depletion to clarify the impact of liver injury on liver metabolism and recovery dynamics of metabolic function and liver zonation during regeneration. Depleting macrophages suppressed tissue remodelling and partially delayed cell proliferation during regeneration after liver injury. In addition, recovery of metabolic functions was delayed by suppressing the tissue remodelling caused by the depleted macrophages. The model revealed that drug metabolic function was resilient against the dysfunction caused by liver injury, but glutamine synthesis was not. Metabolomic analysis revealed that liver branched-chain amino acid (BCAA) and carbohydrate metabolism were suppressed by injury. The plasma BCAA concentration reflected recovery of hepatic function during regeneration. Our study reveals one aspect of the regenerative machinery for hepatic metabolism following acute liver injury.

Highlights

  • The liver is an exclusive organ with tremendous regenerative capacity

  • Using gas chromatography/mass spectrometry (GC/MS)- and conventional analyses, we found that branched-chain amino acid (BCAA) and carbohydrate metabolism were affected by liver injury, and that suppression of tissue remodelling did not lead to adequate recovery of these pathways during liver regeneration

  • The gene expression level of anti-inflammatory macrophage marker Cx3cr[1] was reduced in the clodronate-loaded liposomes (CLOs)-treated mouse liver at 144 h. These results indicate that treating mice with CLO after inducing acute liver injury depletes macrophages in the liver during liver regeneration after injury

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Summary

Introduction

The liver is an exclusive organ with tremendous regenerative capacity. Liver metabolic functions exhibit spatial heterogeneity, reflecting liver zonation. The mechanisms controlling the proliferation of hepatocytes and the accompanying matrix reconstruction during regeneration have been well explored, but the recovery potential of differentiated metabolic functions and zonation after liver injury remains unclear. Depleting macrophages suppressed tissue remodelling and partially delayed cell proliferation during regeneration after liver injury. The tissue architecture is remodelled by hepatic non-parenchymal cells (NPCs)[5] Hepatocytes dynamically remodel their metabolic functions to balance cell division and energy production during liver r­ egeneration[6]. Such changes in liver metabolism are referred to as metabolic remodelling, and contribute to liver regeneration, cell proliferation and tissue remodelling. Liver macrophages are hepatic NPCs that contribute to cell proliferation and tissue remodelling by producing pro-inflammatory cytokines and extracellular matrix (ECM) degradation e­ nzymes[10,11]. The macrophage depletion technique is suitable for investigating tissue remodelling during liver regeneration

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