■非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝病。预后可能会有所不同,从简单的脂肪变性到更严重的结果,如非酒精性脂肪性肝炎(NASH),肝硬化,和肝细胞癌。对导致NASH的生物过程的理解是有限的,并且缺乏非侵入性诊断工具。
■与经活检证实的NAFL(n=35)和NASH患者(n=35)的外周免疫蛋白质组相比,正常体重健康对照(n=15)使用邻近延伸测定法进行研究,结合空间和单细胞肝转录组分析。
■我们确定了13种炎症血清蛋白,独立于合并症和纤维化阶段,区分NASH和NAFL。共表达模式和生物网络的分析进一步揭示了NASH特异性生物扰动,其指示IL-4/-13、-10、-18和非典型NF-κβ信号传导的时间失调。在确定的炎性血清蛋白中,IL-18和EN-RAGE以及ST1A1映射到肝巨噬细胞和门静脉周围肝细胞,分别,在单细胞水平。炎性血清蛋白的特征进一步允许鉴定NASH患者的生物学上不同的亚组。
■NASH患者有明显的炎性血清蛋白特征,可以映射到肝实质,疾病的发病机理,并鉴定肝脏生物学改变的NASH患者亚组。
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking.
The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis.
We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients.
NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology.