Abstract：
OBJECTIVE: Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. The liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH.
METHODS: We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro.
RESULTS: The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells.
CONCLUSIONS: We conclude that HSC-expressed NR1H4 and GSPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals.
UNASSIGNED: Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.
METHODS: We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro.
RESULTS: The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells.
CONCLUSIONS: We conclude that HSC-expressed NR1H4 and GSPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals.
UNASSIGNED: Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.
摘要：
目的：代谢功能障碍相关脂肪性肝炎（MASH）与胰岛素抵抗和2型糖尿病有关，并以肝脏炎症为特征，微血管功能障碍,和纤维化，损害肝功能和加重代谢紊乱。MASH中破坏的肝脏稳态相互作用仍然知之甚少。我们旨在阐明与晚期MASH相关的非实质细胞的可塑性和变化的相互作用。
方法：我们以单细胞分辨率表征了饮食诱导的高级MASH小鼠模型，并通过测定染色质可及性验证了发现，对小鼠和人类肝脏进行生物成像，并通过体内和体外功能实验。
结果：肝星状细胞（HSC）的纤维化激活导致由胆汁酸受体NR1H4/FXR和HSC特异性GS蛋白偶联受体（GSPCRs）组成的信号传导模块的恶化。伴随HSC激活，我们进一步观察到HSCGdf2表达的衰减，和可能来自传入单核细胞和Kupffer细胞的CD207阳性巨噬细胞群的MASH相关扩增。
结论：我们得出结论，健康肝脏的HSC表达的NR1H4和GSPCRs整合了餐后提示，维持HSC静止，通过旁分泌信号，整体正弦健康。因此，MASH中的HSC激活不仅驱动纤维发生，而且可能使肝窦对肝脏稳态信号脱敏。
■肝细胞类型之间的稳态相互作用及其在代谢功能障碍相关脂肪性肝炎中的恶化特征不佳。在我们目前的晚期小鼠代谢功能障碍相关脂肪性肝炎的单细胞解析研究中，我们确定了一个与静止相关的肝星状细胞信号传导模块，具有保持正常正弦功能的潜力。由于其成分的表达水平在人类肝脏中是保守的，刺激识别的信号模块是一个有前途的治疗策略，以恢复慢性肝病的血窦功能。
方法：我们以单细胞分辨率表征了饮食诱导的高级MASH小鼠模型，并通过测定染色质可及性验证了发现，对小鼠和人类肝脏进行生物成像，并通过体内和体外功能实验。
结果：肝星状细胞（HSC）的纤维化激活导致由胆汁酸受体NR1H4/FXR和HSC特异性GS蛋白偶联受体（GSPCRs）组成的信号传导模块的恶化。伴随HSC激活，我们进一步观察到HSCGdf2表达的衰减，和可能来自传入单核细胞和Kupffer细胞的CD207阳性巨噬细胞群的MASH相关扩增。
结论：我们得出结论，健康肝脏的HSC表达的NR1H4和GSPCRs整合了餐后提示，维持HSC静止，通过旁分泌信号，整体正弦健康。因此，MASH中的HSC激活不仅驱动纤维发生，而且可能使肝窦对肝脏稳态信号脱敏。
■肝细胞类型之间的稳态相互作用及其在代谢功能障碍相关脂肪性肝炎中的恶化特征不佳。在我们目前的晚期小鼠代谢功能障碍相关脂肪性肝炎的单细胞解析研究中，我们确定了一个与静止相关的肝星状细胞信号传导模块，具有保持正常正弦功能的潜力。由于其成分的表达水平在人类肝脏中是保守的，刺激识别的信号模块是一个有前途的治疗策略，以恢复慢性肝病的血窦功能。
