Leukocyte cell-derived chemotaxin 2 promotes the development of nonalcoholic fatty liver disease through STAT-1 pathway in mice
Leukocyte cell-derived chemotaxin 2 promotes the development of nonalcoholic fatty liver disease through STAT-1 pathway in mice
复制标题
白细胞来源的趋化因子2通过STAT-1途径促进小鼠非酒精性脂肪肝的发展
DOI：
10.1111/liv.14816
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发表时间：
2021-02-23
影响因子：
6.7
通讯作者：
Xu, Chengfu
中科院分区：
文献类型：
--
作者：
Wang, Jinghua;Chen, Yishu;Xu, Chengfu
背景非酒精性脂肪性肝病（NAFLD）的发病机制尚未阐明，已成为全球日益普遍的疾病，需要新的治疗策略。本研究旨在探讨白细胞源性趋化因子2（leukocellular-derived chemotaxin 2，LECT 2）在NAFLD发生发展中的作用。尾静脉注射含有Lect 2短发夹RNA或Lect 2过表达质粒的腺相关病毒，以抑制或增加肝脏Lect 2表达。通过苏木精-伊红和油红O组织学染色以及定量肝甘油三酯测量来评价肝脂肪变性。结果NAFLD患者和HFD喂养小鼠血清和肝脏中LECT 2水平均升高。抑制肝脏Lect 2表达可减轻HFD诱导的肝脏脂肪变性和炎症，而肝脏Lect 2过表达可加重HFD诱导的肝脏脂肪变性和炎症。RNA-seq和生物信息学分析表明，信号转导和转录激活因子-1（STAT-1）通路可能在LECT 2与NAFLD的相互作用中起着不可或缺的作用。STAT-1抑制剂可逆转Lect 2过表达引起的肝脏脂质蓄积。LECT 2通过STAT-1途径诱导NAFLD的发生和发展。LECT 2可能是NAFLD的潜在治疗靶点。
Background Nonalcoholic fatty liver disease (NAFLD), whose pathogenesis remains unelucidated, has become an increasingly prevalent disease globally requiring novel treatment strategies. This study aims to explore the role of leukocyte cell-derived chemotaxin 2 (LECT2), one of the known hepatokines, in the development of NAFLD.Methods The serum LECT2 level was evaluated in patients with NAFLD and male C57BL/6 mice fed a high-fat diet (HFD) for 8 weeks. Tail intravenous injection of adeno-associated virus that contained Lect2 short hairpin RNA or Lect2 overexpression plasmid was administered to mice to inhibit or increase hepatic Lect2 expression. Hepatic steatosis was evaluated by histological staining with haematoxylin and eosin and Oil Red O, and also by quantitative hepatic triglyceride measurements. RNA-seq was performed to discover the specific targets of LECT2 on NAFLD.Results Serum and hepatic LECT2 levels were elevated in NAFLD patients and HFD-fed mice. Inhibition of hepatic Lect2 expression alleviated HFD-induced hepatic steatosis and inflammation, whereas hepatic overexpression of Lect2 aggravated HFD-induced hepatic steatosis and inflammation. RNA-seq and bioinformatical analysis suggested that the signal transducers and activators of transcription-1 (STAT-1) pathway might play an indispensable role in the interaction between LECT2 and NAFLD. A STAT-1 inhibitor could reverse the accumulation of hepatic lipids caused by Lect2 overexpression.Conclusion LECT2 expression is significantly elevated in NAFLD. LECT2 induces the occurrence and development of NAFLD through the STAT-1 pathway. LECT2 may be a potential therapeutic target for NAFLD.