Figge Anne, Lammert Frank, Paigen Beverly, Henkel Anne, Matern Siegfried, Korstanje Ron, Shneider Benjamin L, Chen Frank, Stoltenberg Erik, Spatz Kathryn, Hoda Farzana, Cohen David E, Green Richard M
Department of Medicine III, University Hospital Aachen, Aachen University, 52074 Aachen, Germany.
J Biol Chem. 2004 Jan 23;279(4):2790-9. doi: 10.1074/jbc.M307363200. Epub 2003 Oct 21.
Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BAC-Abcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7alpha-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.
Abcb11编码肝脏胆汁盐输出泵，该泵对肝胆胆汁盐分泌起限速作用。我们利用转甲状腺素蛋白 - Abcb11和细菌人工染色体 - Abcb11转基因来培育肝脏中胆汁盐输出泵过表达的小鼠。这些小鼠表现出胆汁流量增加以及胆汁盐、磷脂酰胆碱和胆固醇的胆汁分泌增加。胆固醇7α - 羟化酶的肝脏基因表达和顶端钠胆汁盐转运体的回肠表达显著降低，而核胆汁盐受体FXR的靶基因（回肠脂质结合蛋白、短异源二聚体伴侣（SHP））的基因表达增加。由于这些基因表达变化与胆汁盐池总体疏水性增加以及FXR配体牛磺脱氧胆酸盐增加4倍相关，它们反映了胆汁盐介导的对FXR和SHP靶基因的调节。尽管胆汁盐的胆汁分泌增加，但粪便胆汁盐排泄未改变，提示胆汁盐的肠肝循环增强。与野生型对照相比，喂食致石性（高胆固醇/脂肪/胆酸）饮食的Abcb11转基因小鼠肝脂肪变性明显减轻。我们得出结论，过表达Abcb11的小鼠胆汁胆汁盐分泌和牛磺脱氧胆酸盐含量增加，这与FXR/SHP介导的肝脏和回肠基因表达变化相关。由于这些小鼠对肝脏脂质积累具有抗性，Abcb11的调节可能对脂肪性肝炎的发病机制和治疗很重要。
