Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, and Harvard Medical School, Boston, MA, USA.
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, and Harvard Medical School, Boston, MA, USA.
Cell Chem Biol. 2023 Sep 21;30(9):1144-1155.e4. doi: 10.1016/j.chembiol.2023.06.001. Epub 2023 Jun 23.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. We recently discovered that neuronal regeneration-related protein (NREP/P311), an epigenetically regulated gene reprogrammed by parental metabolic syndrome, is downregulated in human NAFLD. To investigate the impact of NREP insufficiency, we used RNA-sequencing, lipidomics, and antibody microarrays on primary human hepatocytes. NREP knockdown induced transcriptomic remodeling that overlapped with key pathways impacted in human steatosis and steatohepatitis. Additionally, we observed enrichment of pathways involving phosphatidylinositol signaling and one-carbon metabolism. Lipidomics analyses also revealed an increase in cholesterol esters and triglycerides and decreased phosphatidylcholine levels in NREP-deficient hepatocytes. Signalomics identified calcium signaling as a potential mediator of NREP insufficiency's effects. Our results, together with the encouraging observation that several single nucleotide polymorphisms (SNPs) spanning the NREP locus are associated with metabolic traits, provide a strong rationale for targeting hepatic NREP to improve NAFLD pathophysiology.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病病因。我们最近发现，神经元再生相关蛋白（NREP/P311）是一种受父母代谢综合征调控的表观遗传基因重编程的蛋白，在人类 NAFLD 中表达下调。为了研究 NREP 不足的影响，我们使用 RNA 测序、脂质组学和抗体微阵列对原代人肝细胞进行了研究。NREP 敲低诱导了转录组重排，与人类脂肪变性和脂肪性肝炎中受影响的关键途径重叠。此外，我们观察到涉及磷脂酰肌醇信号和一碳代谢的途径富集。脂质组学分析还显示胆固醇酯和甘油三酯增加，NREP 缺陷肝细胞中磷脂酰胆碱水平降低。信号组学将钙信号确定为 NREP 不足效应的潜在介质。我们的研究结果，以及横跨 NREP 基因座的几个单核苷酸多态性（SNP）与代谢特征相关的令人鼓舞的观察结果，为靶向肝 NREP 以改善 NAFLD 病理生理学提供了强有力的理由。
