Sandhu Bynvant, Perez Matos Maria C, Tran Stephanie, Zhong Alexander, Csizmadia Eva, Kim Misung, Herman Mark A, Nasser Imad, Lai Michelle, Jiang Z Gordon
Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
JHEP Rep. 2019 Jun 8;1(3):199-202. doi: 10.1016/j.jhepr.2019.05.007. eCollection 2019 Sep.
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 in human liver cells is not known. In this study, we aimed to define the relationship between transcription and disease characteristics of human NAFLD.
The abundance of and collagen 1α () transcripts was quantified at single-cell resolution using RNAscope® in 87 patients with NAFLD. We examined the association of and transcript levels with NAFLD disease severity, defined by histology.
While the majority of transcripts were found in hepatocytes, approximately 7% of -positive cells co-express , representing activated myofibroblasts. There is no association between the rs738409 genotype and the level of transcript. The overall 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 transcript levels and liver fibrosis is largely driven by -positive cells. A significant proportion of mRNA is seen in the nucleus. The cytoplasmic-to-nuclear mRNA ratio is inversely associated with NAFLD disease activity.
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.
A genetic variant in patatin-like phospholipase domain-containing protein 3 (or ) is the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, it is not known how transcriptional regulation of the gene contributes to the disease characteristics of human NAFLD. Herein, we show that the mRNA levels of , particularly in the cytoplasm, are negatively associated with the severity of NAFLD in humans.
含帕他汀样磷脂酶结构域蛋白3（PNPLA3）中的I148M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背景下，人类肝细胞中该基因的转录调控尚不清楚。在本研究中，我们旨在明确该基因转录与人类NAFLD疾病特征之间的关系。
使用RNAscope®以单细胞分辨率对87例NAFLD患者的该基因和胶原蛋白1α1（COL1A1）转录本丰度进行定量。我们研究了该基因和COL1A1转录本水平与经组织学定义的NAFLD疾病严重程度之间的关联。
虽然大多数该基因转录本存在于肝细胞中，但约7%的该基因阳性细胞共表达COL1A1，代表活化的肌成纤维细胞。rs738409基因型与该基因转录本水平之间无关联。该基因转录本的总体丰度在1区肝细胞、体重指数较高的患者以及肝纤维化晚期患者中较低。该基因转录本水平与肝纤维化之间的负相关主要由该基因阳性细胞驱动。在细胞核中可见相当比例的该基因mRNA。该基因mRNA的细胞质与细胞核比例与NAFLD疾病活动度呈负相关。
该基因转录本丰度和细胞核到细胞质的转运与肝脂肪变性和NAFLD疾病活动度呈负相关，而其在活化肌成纤维细胞中的丰度与肝纤维化阶段呈负相关。
含帕他汀样磷脂酶结构域蛋白3（即PNPLA3）中的一种基因变体是非酒精性脂肪性肝病（NAFLD）最重要的遗传决定因素。然而，尚不清楚该基因的转录调控如何影响人类NAFLD的疾病特征。在此，我们表明该基因的mRNA水平，尤其是在细胞质中的水平，与人类NAFLD的严重程度呈负相关。
