胆汁酸结肠炎.doc

PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis by14211 1.摘要 胆汁酸在炎症性肠道疾病（IBD）中发挥着重要作用，但胆汁酸IBD中失调的机制仍是未知。本文指出PPARα（过氧化物酶体增值物激活受体）-UGTs（葡萄糖醛酸转移酶）信号对胆汁酸体内平衡起着重要的决定作用。葡聚糖硫酸钠（DSS）诱导的结肠炎通过激活过氧化物酶体增值物激活受体PPARα-UGTs途径，导致胆汁酸在发炎的结肠组织中积累。UGTs加速胆汁酸的清除和代谢，从而降低其在小肠中的胞内水平。细胞内胆汁酸的降低使法尼醇X受体(FXR) -FGF15信号的减弱，导致肝CYP7A1的上调，从而促进胆汁酸的从头合成。PPARα的敲除和用重组FGF19治疗都能显著减轻DSS诱导的结肠炎。因此，本文推测，肠PPARα-UGTs和下游FXR-FGF15信号通路对胆汁酸体内平衡起重要的决定作用，并在结肠炎的病理发展中发挥重要作用。 回肠中OEA激活PPARα，上调UGTs的作用，增加胆汁酸的代谢清除。FXR內源性配体胆汁酸在小肠细胞内的水平减少，减弱了回肠FXR-FGF15的信号，导致肝CYP7A1的连续激活，并因此增加胆汁酸的从头合成，最后导致胆汁酸在发炎的结肠组织中积累。 2.基本介绍 2.1结肠炎中结肠胆汁酸累积 通过对DSS造模组的胆汁酸水平的观察发现：与正常鼠比，结肠炎小鼠胆汁酸池较大，表明胆汁酸从头合成增加；与正常鼠比，结肠炎小鼠血清中胆汁酸浓度较低，而在胆囊、小肠、结肠和粪便中较高。 Figure 1 | DSS-induced colitis disrupts bile acids homeostasis. (a) Bile acid pool analysis. The bile acid pool size was analysed by measuring total bile acids in the whole enterohepatic system, including the liver, gall bladder and the entire small intestine and its contents, and the values were normalized by body weight. (b–e) Total amount of bile acids in individual compartments. 2.2结肠炎中肝CYP7A1上调 通过对DSS造模组的胆汁酸水平的观察发现：与正常鼠比，结肠炎小鼠胆汁酸池较大，表明胆汁酸从头合成增加；与正常鼠比，结肠炎小鼠血清中胆汁酸浓度较低，而在胆囊、小肠、结肠和粪便中较高。 Figure 1 | DSS-induced colitis disrupts bile acids homeostasis. (a) Bile acid pool analysis. The bile acid pool size was analysed by measuring total bile acids in the whole enterohepatic system, including the liver, gall bladder and the entire small intestine and its contents, and the values were normalized by body weight. (b–e) Total amount of bile acids in individual compartments. 2.3结肠炎中FXR-FGF15信号减弱 与正常组比，结肠炎小鼠回肠中 Fxr的mRNA和蛋白含量没有明显变化，但FXR靶基因Fgf15和Shp的mRNA含量显著减少；免疫染色也表明回肠FGF15蛋白含量明显降低。 Figure 2 | The intestinal FXR-FGF15 signalling is compromised in colitis. (c–e) Expression of Fxr, Fgf15 and Shp mRNAs in the distal ileum. (f) Expression of Fgfr4 and b-Klotho mRNAs in the liver. (g) Immunohistochemistry staining and quantitative analysis of FXR pro