Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
Cell Mol Gastroenterol Hepatol. 2022;13(1):151-171. doi: 10.1016/j.jcmgh.2021.08.002. Epub 2021 Aug 11.
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH.
A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus-Cxcl1 overexpression (HFD). Genetic deletion of E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model.
By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD mice. The HFD-induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice.
E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.
非酒精性脂肪性肝炎（NASH）是一种主要的慢性肝病病因，其特征为脂肪变性和标志性的肝脏中性粒细胞浸润。NASH 还与脂肪组织炎症相关，但脂肪组织炎症在 NASH 发病机制中的作用仍不清楚。本研究旨在研究脂肪组织中性粒细胞募集与 NASH 进展之间的相互作用。
通过高脂肪饮食（HFD）喂养加腺病毒-Cxcl1 过表达（HFD）建立 NASH 小鼠模型。使用该模型研究 E-选择素（Sele）的基因缺失和 S100A9 抑制剂（Paquinimod）的治疗作用。
通过分析 NASH 患者脂肪组织的转录组数据集，我们发现与单纯脂肪变性患者相比，E-选择素（中性粒细胞募集相关因子中上调最高的关键黏附分子）在 NASH 患者脂肪组织中上调程度最高。在 HFD 小鼠中也观察到脂肪组织中 Sele 的显著上调。Sele 敲除小鼠的 HFD 诱导的 NASH 表型得到改善，同时脂肪组织中的脂肪分解和炎症减少，导致血清游离脂肪酸和促炎脂肪因子减少。S100A8/A9，一种中性粒细胞分泌的主要促炎蛋白，在 HFD 小鼠的脂肪组织中高度增加。这种增加在 Sele 敲除小鼠中减弱。治疗上，S100A9 抑制剂 Paquinimod 治疗可减少脂肪分解、炎症和脂肪因子产生，从而改善小鼠的 NASH 表型。
E-选择素在诱导脂肪组织中性粒细胞募集中起重要作用，随后通过产生 S100A8/A9 促进炎症和脂肪分解，从而加剧脂肪变性向 NASH 的进展。因此，靶向脂肪组织炎症可能代表治疗 NASH 的一种潜在新疗法。
