Shen Nan, Tang Ling, Qian Yufan, Pan Jielu, Pan Jiashu, Miao Hongyu, Zhang Haiyan, Fang Hong, Yu Xiao, Xing Lianjun
Department II of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Preventive Health Department of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Ann Transl Med. 2023 Feb 28;11(4):173. doi: 10.21037/atm-22-6620. Epub 2023 Feb 21.
In lean individuals, nonalcoholic fatty liver disease (NAFLD) is not a benign disease, and these patients have long-term morbidity and mortality similar to those of their nonlean counterparts. Finding biomarkers for noninvasive and early detection is urgent and microRNAs (miRNAs) show potential. The aims of this study were to investigate the potential role of serum miRNAs in the detection of lean NAFLD and to explore the possible pathogenesis of lean NAFLD.
A total of 498 patients with NAFLD and 98 healthy controls were included to compare the clinical characteristics of lean NAFLD patients [LNs: body mass index (BMI) <23 kg/m], nonlean NAFLD patients (NLNs: BMI ≥23 kg/m) and normal healthy individuals (HIs). A total of 14 serum samples were collected from 4 LNs, 6 NLNs and 4 HIs for high-throughput profiling to identify altered miRNA expression patterns in lean NAFLD. The candidate miRNA, miR-4488, was identified by filtering based on studies in a second independent cohort (31 LNs, 62 NLNs, 72 HIs) that included quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction network analyses were performed to investigate the potential molecular mechanism of miR-4488 in lean NAFLD.
LNs were older and had a smaller waist circumference, lower levels of alanine aminotransferase, glutamyl transpeptidase, fasting insulin, and uric acid, lower HOMA-IR score, and higher levels of total cholesterol, high-density lipoprotein cholesterol, and hemoglobin (P<0.05). The serum level of miR-4488 was increased in LNs compared with HIs (P<0.0001) and NLNs (P=0.025). miR-4488 had acceptable performance in predicting [area under the curve (AUC) =0.794, 0.698] lean NAFLD. Moreover, GO and KEGG enrichment analyses revealed that the differentially expressed target genes were mainly involved in choline metabolism in cancer, the tumor-necrosis factor (TNF) signaling pathway and the p53 signaling pathway. PPI analysis identified ARHGAP1, SLC10A1 and SIX5 as the hub genes.
Taken together, our findings indicate that serum miR-4488 is a potential biomarker for diagnosing and predicting the pathogenetic mechanisms of lean NAFLD.
在体型偏瘦的个体中，非酒精性脂肪性肝病（NAFLD）并非良性疾病，这些患者的长期发病率和死亡率与体型不瘦的患者相似。寻找用于无创和早期检测的生物标志物迫在眉睫，而微小RNA（miRNA）显示出了潜力。本研究的目的是探讨血清miRNA在检测体型偏瘦的NAFLD中的潜在作用，并探索体型偏瘦的NAFLD的可能发病机制。
共纳入498例NAFLD患者和98例健康对照，以比较体型偏瘦的NAFLD患者[LNs：体重指数（BMI）<23kg/m²]、体型不瘦的NAFLD患者（NLNs：BMI≥23kg/m²）和正常健康个体（HIs）的临床特征。从4例LNs、6例NLNs和4例HIs中收集了14份血清样本进行高通量分析，以鉴定体型偏瘦的NAFLD中miRNA表达模式的改变。通过在第二个独立队列（31例LNs、62例NLNs、72例HIs）中基于研究进行筛选，并包括定量实时聚合酶链反应（qRT-PCR）分析，鉴定出候选miRNA miR-4488。进行基因本体（GO）富集、京都基因与基因组百科全书（KEGG）富集以及蛋白质-蛋白质相互作用网络分析，以研究miR-4488在体型偏瘦的NAFLD中的潜在分子机制。
LNs年龄较大，腰围较小，丙氨酸氨基转移酶、谷氨酰转肽酶、空腹胰岛素和尿酸水平较低，HOMA-IR评分较低，总胆固醇、高密度脂蛋白胆固醇和血红蛋白水平较高（P<0.05）。与HIs（P<0.0001）和NLNs（P=0.025）相比，LNs中miR-4488的血清水平升高。miR-4488在预测体型偏瘦的NAFLD方面具有可接受的性能[曲线下面积（AUC）=0.794，0.698]。此外，GO和KEGG富集分析表明，差异表达的靶基因主要参与癌症中的胆碱代谢、肿瘤坏死因子（TNF）信号通路和p53信号通路。蛋白质-蛋白质相互作用分析确定ARHGAP1、SLC10A1和SIX5为枢纽基因。
综上所述，我们的研究结果表明血清miR-4488是诊断和预测体型偏瘦的NAFLD发病机制的潜在生物标志物。
