Neuregulin 4在非酒精性脂肪肝中减少肝脏脂肪沉积的机制研究

No effective and safe pharmacological drug for non-alcoholic fatty liver disease (NAFLD) has been approved so far. Recent studies have shown that neuregulin 4 (NRG4), a novel found protein that was preferentially secreted from brown and/or beige adipocytes, was effective in reducing liver-fat content in the state of NAFLD. However, the mechanism remains unclear. Enhanced mesenteric fat lipolysis, which is mainly drained through the portal vein to the liver, promotes obesity-associated hepatic steatosis. Fibroblast growth factor 21 (FGF21), with the liver as the predominant site for production and the adipose tissue as the main target of its actions, plays an important role in modulating lipolysis. Our previous work indicated that NRG4 intervention significantly reduced liver-fat content and also reduced basal lipolysis in portally drained mesenteric adipocytes in mice with NAFLD. FGF21 mRNA levels in the liver and its protein release were significantly increased after NRG4 intervention. NRG4 stimulation had little effect on lipolysis in 3T3L1 cells. FGF21 released from HepG2 cells is required for NRG4-induced lipolysis in 3T3L1 cells. It is hypothesized that FGF21 coupled NRG4 actions in portally drained mesenteric adipocytes, thereby mediating the effects of NRG4 on the reduction of liver-fat content. In this study, we will make every effort to clarify the potential molecular biological mechanisms underlying the effect of NRG4 on reducing the liver-fat content. It is expected to offer new theoretical and experimental basis for the application of NRG4 as a candidate for the treatment for NAFLD.

目前，非酒精性脂肪肝（NAFLD）尚缺乏有效的治疗药物。研究显示，新发现的棕色和/或褐色脂肪细胞因子neuregulin 4（NRG4）能明显减少肝脏脂肪沉积，但机制尚未阐明。肠系膜脂肪组织（MAT）脂解增强时，大量游离脂肪酸直接外溢至肝脏，诱发NAFLD。FGF21对脂解起着重要的调控作用。我们前期研究发现，在NAFLD小鼠中，给予重组人NRG4蛋白干预后，MAT的基础脂解率明显降低，血浆FGF21蛋白及肝脏FGF21 mRNA的水平明显升高，肝脏脂肪沉积明显减少；NRG4不能直接抑制3T3L1脂肪细胞脂解，肝细胞分泌的FGF21可介导其发挥抑制脂解作用。据此推测：NRG4通过促进肝脏FGF21表达，抑制MAT脂解，从而减少肝脏脂肪沉积。本课题拟从MAT脂解入手，通过体内外实验探讨NRG4减少肝脏脂肪沉积的分子生物学机制，为认识NRG4改善NAFLD的作用和机制提供新的理论和实验依据。

目前，非酒精性脂肪肝（NAFLD）尚缺乏有效的治疗药物。研究显示，新发现的棕色和/或.褐色脂肪细胞因子neuregulin 4（NRG4）能明显减少肝脏脂肪沉积，但机制尚未阐明。肝脏对游离脂肪酸（FFA）的摄取增加是导致肝脏脂肪沉积的首要步骤和主要原因。脂肪酸转位酶（CD36）是介导肝细胞摄取FFA的重要分子，与NAFLD的发生发展密切相关。我们发现给予重组人NRG4蛋白干预后，肝脏CD36表达水平降低，肝脏脂肪沉积减少。据此推测NRG4可通过CD36通路改善脂肪脂肪沉积。本项目中，我们通过在体及离体模型，综合运用分子生物学、形态学及干扰 RNA 等一系列方法，证实1）NAFLD模型中，CD36的基因及蛋白表达水平升高；2）NAFLD模型中，NRG4可减少CD36的表达，并可改善肝脏脂肪沉积，过表达CD36或CD36 RNAi可减弱或增强这一效应；3）揭示NRG4减少NAFLD中肝脏脂肪沉积的分子机制：在NAFLD模型中，NRG4通过上调肝脏STAT5通路（STAT5为NRG4特异性配体ErBb4的下游分子，同时也为CD36的上游分子， 且与肝脏脂质沉积密切相关），抑制肝细胞CD36的表达，减少FFA摄取，进而改善脂肪肝。本项目将为NRG4改善NAFLD肝脏脂肪沉积的机制研究提供新的理论和实验依据，并有望为NAFLD的防治提供新的治疗靶点。