General Research Institute, Nihon University Collage of Bioresource Sciences, Fujisawa, Kanagawa, 252-0880, Japan.
Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, 252-0880, Japan.
Sci Rep. 2021 May 6;11(1):9730. doi: 10.1038/s41598-021-88989-9.
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 (CCl) 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.
肝脏是一个具有巨大再生能力的独特器官。肝脏的代谢功能表现出空间异质性，反映了肝的分带现象。控制肝细胞增殖和伴随的基质重建的机制在再生过程中已经得到了很好的探索，但肝损伤后分化代谢功能和分带的恢复潜力仍不清楚。我们采用四氯化碳（CCl）诱导的急性肝损伤小鼠模型和氯膦酸盐诱导的巨噬细胞耗竭来阐明肝损伤对肝代谢的影响，以及在再生过程中代谢功能和肝分带恢复的动力学。巨噬细胞耗竭抑制了组织重塑，并在肝损伤后再生过程中部分延迟了细胞增殖。此外，抑制耗竭的巨噬细胞引起的组织重塑会延迟代谢功能的恢复。该模型表明，药物代谢功能对肝损伤引起的功能障碍具有弹性，但谷氨酰胺合成则不然。代谢组学分析显示，肝支链氨基酸（BCAA）和碳水化合物代谢受到损伤的抑制。血浆 BCAA 浓度反映了再生过程中肝功能的恢复。我们的研究揭示了急性肝损伤后肝代谢再生机制的一个方面。
