Martínez-Sánchez Celia, Bassegoda Octavi, Deng Hongping, Almodóvar Xènia, Ibarzabal Ainitze, de Hollanda Ana, Martínez García de la Torre Raquel-Adela, Blaya Delia, Ariño Silvia, Jiménez-Esquivel Natalia, Aguilar-Bravo Beatriz, Vallverdú Julia, Montironi Carla, Osorio-Conles Oscar, Fundora Yiliam, Sánchez Moreno Francisco Javier, Gómez-Valadés Alicia G, Aguilar-Corominas Laia, Soria Anna, Pose Elisa, Juanola Adrià, Cervera Marta, Perez Martina, Hernández-Gea Virginia, Affò Silvia, Swanson Kelly S, Ferrer-Fàbrega Joana, Balibrea Jose Maria, Sancho-Bru Pau, Vidal Josep, Ginès Pere, Smith Andrew M, Graupera Isabel, Coll Mar
Fundació de Recerca Clínic Barcelona-Institut d'Investigacións Biomèdiques August Pi i Sunyer (FCRB-IDIABPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
JHEP Rep. 2023 Jun 27;5(10):100830. doi: 10.1016/j.jhepr.2023.100830. eCollection 2023 Oct.
BACKGROUND & AIMS: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model.
Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed.
Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. , the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids.
Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.
We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.
肥胖状态下脂肪组织巨噬细胞（ATM）的积聚与肝损伤有关。然而，ATM在非酒精性脂肪性肝病（NAFLD）肝纤维化中的作用仍有待阐明。在此，我们研究了NAFLD患者中ATM与肝纤维化之间的关系，并在实验性非酒精性脂肪性肝炎（NASH）模型中评估了调节ATM对肝纤维化的影响。
收集42例不同纤维化阶段的NAFLD患者的脂肪组织和肝活检样本。通过免疫组织化学和流式细胞术对ATM进行表征，并评估ATM与肝纤维化阶段之间的相关性。在饮食诱导的肥胖和NASH小鼠模型中，通过给予葡聚糖偶联地塞米松实现对ATM表型的选择性调节。通过组织学和脂肪组织及肝脏样本中的基因表达分析评估长期给药效果。进行了人ATM与肝星状细胞（HSC）及肝球状体之间的相互作用研究。
NAFLD患者中促炎性ATM的积聚增加，且与肝纤维化相关。对ATM的长期调节显著降低了促炎表型并改善了脂肪组织炎症。此外，在实验性NASH模型中，ATM调节与脂肪变性和肝脏炎症的改善相关，并显著降低了纤维化进展。用葡聚糖 - 地塞米松处理降低人ATM的促炎表型，减少了炎性趋化因子的分泌，并直接减弱了HSC和肝球状体中的促纤维化反应。
NAFLD患者中促炎性ATM与纤维化程度平行增加，在实验性NASH模型中对其进行调节可改善肝纤维化，揭示了ATM作为减轻NAFLD肝纤维化治疗靶点的潜力。
我们报道了在非酒精性脂肪性肝病（NAFLD）中，人脂肪组织促炎性巨噬细胞与肝纤维化相关。此外，在非酒精性脂肪性肝炎实验小鼠模型中，葡聚糖纳米载体偶联地塞米松对脂肪组织巨噬细胞（ATM）的调节将ATM的促炎表型转变为抗炎表型。这种转变改善了脂肪组织炎症、肝脏炎症和纤维化。我们的结果突出了脂肪组织在NAFLD病理生理学中的相关性，并揭示了ATM作为NAFLD潜在靶点的作用。
