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长链非编码RNA与非酒精性脂肪性肝病

作者:未知

  [摘要] 非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)已是世界范围内最常见的慢性肝病之一,可从单纯性脂肪肝发展为伴有炎症浸润及肝损伤的非酒精性脂肪性肝炎、肝纤维化、肝硬化甚至肝癌,但对于其发病机制目前尚未完全清楚。越来越多研究表明长链非编码RNA在NAFLD进展中发挥重要作用,该文主要综述了长链非编码RNA(long non-coding RNA,LncRNA)在NAFLD机制中的主要作用,为lncRNA在NAFLD诊断、治疗及监测的提供新的观点。
  [关键词] 长链非编码RNA;非酒精性脂肪性肝病;脂质代谢;胰岛素抵抗
  [中图分类号] R575          [文献标识码] A          [文章编号] 1674-0742(2019)09(b)-0196-03
  Long-chain Non-coding RNA and Nonalcoholic Fatty Liver Disease
  LIU Si-qi1, LAO Ya-ling, YANG Hong-ju
  Department of Gastroenterology, the First Affiliated Hospital of Kunming Medical University,Kunming, Yunnan Province, 650032 China
  [Abstract] Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world. It can be developed from simple fatty liver to non-alcoholic fatty hepatitis, liver fibrosis, cirrhosis and even liver cancer with inflammatory infiltration and liver damage , but its pathogenesis is not fully understood. More and more studies have shown that long-chain non-coding RNA plays an important role in the progression of NAFLD. This paper reviews the main role of long non-coding RNA (LncRNA) in the mechanism of NAFLD, and providing new perspectives for the diagnoses treatment and monitoring of lncRNA in NAFLD.
  [Key words] Long-chain non-coding RNA; Nonalcoholic fatty liver disease; Lipid metabolism; Insulin resistance
  非酒精性脂肪性肝病(Non-alcoholic fatty liver disease,NAFLD)作為代谢综合征(metabolic syndrome,MetS)在肝脏的表现,与肥胖、胰岛素抵抗(IR)、糖尿病、高脂血症等代谢异常具有密切的联系[1],其疾病谱包括从单纯的肝脏脂肪变性、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)、肝纤维化,甚至可以进展成肝硬化和肝癌[2]。全球约有接近24%的成年人患NAFLD,已成为全球慢性肝病的最常见病因,在亚洲NAFLD在人群中的发病率为27%,仅次于发病率最高(32%)的中东,NASH已成为肝移植的第二大病因,对世界公共健康造成了巨大的威胁[3]。
  长链非编码RNA(Long non-coding RNA,LncRNA)是由一类长度超过200个核苷酸组成的转录本,不具有编码蛋白质的能力但具有一些蛋白质编码mRNA典型特征[4],且参与许多生物学过程,包括细胞多样性、肿瘤的激活、免疫应答等[5-6]lncRNA的突变和调节异常与人类各种复杂疾病密切相关,如前列腺癌、大肠癌、肺癌、AD(阿尔兹海默病)、心血管疾病、白血病、糖尿病和神经退行性病变等[7]。近年越来越多研究证实LncRNA参与了肝脏内脂质代谢[8-9],可能与肝纤维化及肝内炎症有关,在NAFLD的发病中起重要作用[10-12]。
  1 LncRNA与肝脏脂质代谢
  NAFLD是一种以脂质堆积致肝实质细胞脂肪变性和脂肪贮积为特征的临床病理综合征,研究表明,LncRNAs在肝脏脂质代谢的多个生物过程如甘油三酯水平的代谢、胆固醇的合成调节中起着重要的作用。NAFLD 的肝细胞脂肪生成是通过激活LXR-SREBP1c信号通路被异常诱导合成,Zhao等人[13]应用qPCR技术证实肝脏特异性的LncRNA Blnc 1在肥胖及NAFLD模型小鼠体内高表达,且抑制Blnc 1的表达可缓解肝脏脂肪变性及胰岛素抵抗。
  Li等人[5]的研究结果提示Lnc LSTR通过调节TDP-43/FXR/apoC2依赖的信号通路保持机体脂代谢的稳态,Sallam[14]的研究结果表明LeXis在高脂餐喂养的小鼠体内表达增高,升高或者降低LeXis在肝脏中的水平都会影响与胆固醇合成和肝脏内或血浆中胆固醇水平的改变有关的基因表达。Chen等人[11]通过建立敲除了LncRNA-SRA的小鼠模型在动物模型及结合在细胞培养证实了LncRNA-SRA是脂肪细胞和肝脏脂肪形成的调节因子。同时,有研究表明LncRNA-MALAT1的表达异常与NAFLD疾病的严重程度相关,且还参与了肝脏纤维化及炎症的调节[15]。   2  LncRNA与胰岛素抵抗
  肝脏作为全身代谢的主要器官对维持糖脂代谢稳态起重要作用,肝脏的异常代谢促进胰岛素抵抗的产生[16],而以胰岛素抵抗为特征的MetS是NAFLD与NASH的独立危险因素,能增加NAFLD的患病风险,同时NAFLD也会增强MetS的临床症状及并发症的发生[17]。胰岛素抵抗为代谢综合征的中心环节[18],逐年增多的研究数据表明,LncRNA作为基因表达调控的关键因子在胰岛素信号传递及胰岛素抵抗之间起重要的作用,尤其对胰岛素作用的靶组织肝脏[19]。
  LncRNA-MEG3在高脂餐诱导的小鼠体内表达上调且通过增强FoxO1(一种肝脏糖脂代谢的调控因子)的表达增加肝脏内胰岛素抵抗[20]。Yan等人[10]的研究结果表明LncRNA-MALAT1能通过增加SREBP-1c核蛋白的稳定性增强胰岛素抵抗。一项关于[21]LncRNA与2型糖尿病的相关性研究表明,异常表达的LncRNA可能通过参与了慢性炎症及胰岛素抵抗的调控在2型糖尿病的发病机制中发挥作用,且与代谢综合征相关指标BMI、FPG、2 hPG、HbA1c、HDL-C、HOMA-IR等密切相关。
  3  LncRNA与肝细胞癌
  NAFLD是导致肝细胞癌(hepatocellular carcinoma,HCC)最重要的病因,也是HCC的獨立预测因素,目前越来越的文献报道NAFLD-HCC可不经历肝硬化阶段而发病[22],同时 LncRNA在HCC进展中的调控作用也被大量研究报道。LncRNA-CCAT1、Linc00462被证实与正常肝组织相比,在HCC组织中显著上调,敲除linc00462基因会使致癌基因表型表达减弱,高表达的CCTA1与肝癌细胞的增殖、转移密切相关[12, 23]。此外,LncRNA,例如HOTAIR[24]、CRNDE[25]、SNHG7、 PVT1[26]在HCC细胞侵入及增殖扩散也起至关重要的作用。Ji等筛选出与肿瘤相关的41条lncRNA,并通过利用GO分析证实Linc01615通过对细胞外基质的潜在作用而在HCC肿瘤转移中产生影响[27]。
  4  小结与展望
  近年来,随着基因测序技术的迅猛发展,非编码RNA在疾病中的作用逐渐被重视,虽然LncRNA在NAFLD发病机制中的研究日益增多,但其作用机制尚未完全清楚。目前NAFLD的诊断仍缺乏特异性,而非编码RNAs可以形成稳定的二次结构,并可在体外循环中被检测到,故在很大程度上它们作为非侵入性生物标记还有更多的探索潜力[28],进一步探索LncRNA在NAFLD发生发展中的作用机制,将对疾病的筛查、监测、诊断及治疗产生重要意义。
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  (收稿日期:2019-06-21)
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