Changes in Hepatic Gene Expression upon Oral Administration of Taurine-Conjugated Ursodeoxycholic Acid in ob/ob Mice

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with considerable morbidities. Unfortunately, there is no currently available drug established to treat NAFLD. It was recently reported that intraperitoneal administration of taurine-conjugated ursodeoxycholic acid (TUDCA) improved hepatic steatosis in ob/ob mice. We hereby examined the effect of oral TUDCA treatment on hepatic steatosis and associated changes in hepatic gene expression in ob/ob mice. We administered TUDCA to ob/ob mice at a dose of 500 mg/kg twice a day by gastric gavage for 3 weeks. Body weight, glucose homeostasis, endoplasmic reticulum (ER) stress, and hepatic gene expression were examined in comparison with control ob/ob mice and normal littermate C57BL/6J mice. Compared to the control ob/ob mice, TUDCA treated ob/ob mice revealed markedly reduced liver fat stained by oil red O (44.2±5.8% vs. 21.1±10.4%, P<0.05), whereas there was no difference in body weight, oral glucose tolerance, insulin sensitivity, and ER stress. Microarray analysis of hepatic gene expression demonstrated that oral TUDCA treatment mainly decreased the expression of genes involved in de novo lipogenesis among the components of lipid homeostasis. At pathway levels, oral TUDCA altered the genes regulating amino acid, carbohydrate, and drug metabolism in addition to lipid metabolism. In summary, oral TUDCA treatment decreased hepatic steatosis in ob/ob mice by cooperative regulation of multiple metabolic pathways, particularly by reducing the expression of genes known to regulate de novo lipogenesis.

非酒精性脂肪性肝病（Nonalcoholic fatty liver disease, NAFLD）患病率极高，且与多种严重并发症密切相关。遗憾的是，目前尚无获批用于治疗NAFLD的药物。近期有研究报道，腹腔给予牛磺熊去氧胆酸（taurine-conjugated ursodeoxycholic acid, TUDCA）可改善ob/ob小鼠的肝脏脂肪变性。本研究考察了口服TUDCA对ob/ob小鼠肝脏脂肪变性及肝脏基因表达相关变化的影响。我们以500 mg/kg的TUDCA剂量，每日两次通过灌胃方式对ob/ob小鼠给药，持续3周。以对照组ob/ob小鼠及正常同窝C57BL/6J小鼠作为对照，检测各组小鼠的体重、葡萄糖稳态、内质网（ER）应激及肝脏基因表达情况。与对照组ob/ob小鼠相比，经TUDCA处理的ob/ob小鼠经油红O染色后的肝脏脂肪含量显著降低（44.2±5.8% vs. 21.1±10.4%，P<0.05）；而两组小鼠的体重、口服葡萄糖耐量、胰岛素敏感性及内质网应激水平均无显著差异。肝脏基因表达的基因芯片分析显示，在脂质稳态相关组分中，口服TUDCA治疗主要下调了参与从头脂肪生成的基因的表达。在通路层面，口服TUDCA除调控脂质代谢相关基因外，还改变了氨基酸、碳水化合物及药物代谢相关基因的表达。综上，口服TUDCA可通过协同调控多条代谢通路，尤其是下调已知参与从头脂肪生成的基因的表达，改善ob/ob小鼠的肝脏脂肪变性。