Quantitative digital pathology reveals association of cell-specific PNPLA3 transcription with NAFLD disease activity
Quantitative digital pathology reveals association of cell-specific PNPLA3 transcription with NAFLD disease activity
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DOI：
10.1016/j.jhepr.2019.05.007
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发表时间：
2019-09-01
期刊：
影响因子：
8.3
通讯作者：
Jiang, Z. Gordon
中科院分区：
文献类型：
--
作者：
Sandhu, Bynvant;Matos, Maria C. Perez;Jiang, Z. Gordon
背景和目标：马铃薯糖蛋白样磷脂酶结构域蛋白3（PNPLA 3）中的I148 M变体（rs738409）是迄今为止非酒精性脂肪性肝病（NAFLD）最重要的遗传决定因素。然而，在NAFLD的情况下，PNPLA 3在人肝细胞中的转录调控是未知的。在这项研究中，我们的目的是确定PNPLA 3转录和人类NAFLD的疾病特征之间的关系。方法：PNPLA 3和胶原1 α（COL 1 α）转录的丰度在87例NAFLD患者中使用RNA-scope（R）以单细胞分辨率原位定量。我们研究了PNPLA 3和COL 1 α转录水平与NAFLD疾病严重程度的关联，定义由histologic.Results：虽然大多数PNPLA 3转录发现在肝细胞，约7%的PNPLA 3阳性细胞共表达COL 1 α，代表激活的肌成纤维细胞。rs738409基因型与PNPLA 3转录水平之间无相关性。总体PNPLA 3转录丰度在1区肝细胞、具有较高体重指数的患者和具有晚期肝纤维化的患者中较低。PNPLA 3转录水平与肝纤维化之间的负相关性主要由COL 1 α阳性细胞驱动。在细胞核中观察到显著比例的PNPLA 3 mRNA。细胞质与核PNPLA 3 mRNA的比例与NAFLD疾病activity.Conclusions呈负相关：PNPLA 3转录丰度和核质易位与肝脂肪变性和NAFLD疾病活动呈负相关，而其在活化的肌成纤维细胞中的丰度与肝纤维化的阶段呈负相关。(C)2019作者（S）由Elsevier B. V.代表欧洲肝脏研究协会（EASL）发表。
Background & Aims: The I148M variant (rs738409) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is by far the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, in the context of NAFLD, the transcriptional regulation of PNPLA3 in human liver cells is not known. In this study, we aimed to define the relationship between PNPLA3 transcription and disease characteristics of human NAFLD.Methods: The abundance of PNPLA3 and collagen 1 alpha (COL1 alpha) transcripts was quantified in situ at single-cell resolution using RNA-scope (R) in 87 patients with NAFLD. We examined the association of PNPLA3 and COL1 alpha transcript levels with NAFLD disease severity, defined by histology.Results: While the majority of PNPLA3 transcripts were found in hepatocytes, approximately 7% of PNPLA3-positive cells co-express COL1 alpha, representing activated myofibroblasts. There is no association between the rs738409 genotype and the level of PNPLA3 transcript. The overall PNPLA3 transcript abundance is lower in zone 1 hepatocytes, patients with higher body mass index, and those with advanced liver fibrosis. The negative association between the PNPLA3 transcript levels and liver fibrosis is largely driven by COL1 alpha-positive cells. A significant proportion of PNPLA3 mRNA is seen in the nucleus. The cytoplasmic-to-nuclear PNPLA3 mRNA ratio is inversely associated with NAFLD disease activity.Conclusions: PNPLA3 transcript abundance and nuclear-to-cytoplasmic translocation are negatively associated with hepatic steatosis and NAFLD disease activity, while its abundance in activated myofibroblasts is inversely associated with the stage of liver fibrosis. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).