General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Departments of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Oct;1865(10):158765. doi: 10.1016/j.bbalip.2020.158765. Epub 2020 Jul 11.
BACKGROUND & AIMS: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients.
The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02-1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03-1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07-2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24-3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05).
NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.
神经降压素（NTS）是一种 13 个氨基酸的肽，存在于中枢神经系统和胃肠道中，参与脂质代谢，并通过与神经降压素受体 1（NTSR1）结合促进各种癌症的发生。前神经降压素（pro-NTS），即神经降压素的稳定前体，其血浆水平升高与 2 型糖尿病（T2D）、心血管疾病和代谢相关脂肪性肝病（MAFLD）有关。我们旨在评估：1）1166 名 MAFLD 欧洲个体中神经降压素 rs1800832 和 NTSR1 rs6090453 遗传变异对肝损伤的影响；2）NTS 变异与循环 pro-NTS 的关系；3）125 名肥胖症患者肝组织中 NTS 的 RNAseq 转录组分析。
NTS rs1800832 的 G 等位基因与肝纤维化（比值比（OR）1.27，95%置信区间（CI）1.02-1.58；p=0.03）相关，在携带 NTS 和 NTSR1 G 风险等位基因的个体中更为明显（OR 1.17，95%CI 1.03-1.34；p=0.01），与肝硬化（OR 1.58，95%CI 1.07-2.34；p=0.02）和 HCC（OR 1.98，95%CI 1.24-3.2；p=0.004）相关。循环 pro-NTS 水平与 T2D（p=0.005）、BMI（p=0.04）、年龄（p=0.0016）、肝小叶炎症（p=0.0025）、纤维化>2（p<0.0001）、肝硬化（p=0.0009）和 HCC（p<0.0001）相关，在按 NTS G 等位基因分层后更为明显。转录组数据显示，肝 NTS 表达与纤维生成基因相关（p<0.05）。
NTS rs1800832 变异与 MAFLD 患者的晚期纤维化和 HCC 相关，可能影响 NTS 蛋白活性。NTSR1 基因 rs6090453 变异与 NTS rs1800832 突变协同作用，促进肝损伤。需要前瞻性研究来证实 NTS 在肝病进展中的作用。
