Fujita Kyosuke, Iguchi Yusuke, Une Mizuho, Watanabe Shiro
Division of Nutritional Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Faculty of Pharmaceutical Science, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
Lipids. 2017 Apr;52(4):335-344. doi: 10.1007/s11745-017-4242-5. Epub 2017 Mar 17.
The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.
法尼酯X受体（FXR）是胆汁酸的主要核受体；其激活可抑制固醇调节元件结合蛋白1c（SREBP1c）介导的脂肪生成，并降低肝脏中的脂质含量。有许多报道表明，给予熊去氧胆酸（UDCA）可抑制脂肪生成并降低实验动物肝脏中的脂质含量。由于UDCA不被认为是一种FXR激动剂，UDCA的这些作用不能通过其直接激活FXR来轻易解释。我们观察到，在小鼠饮食中给予UDCA可降低SREBP1c及其靶标脂肪生成基因的表达水平。α-和β-鼠胆酸（MCA）以及胆酸（CA）是小鼠肝脏中的主要胆汁酸，但在给予UDCA后它们的含量降低。鹅去氧胆酸和脱氧胆酸（DCA）在肝脏中的含量相对较低，但不受UDCA影响。在体外FXR反式激活试验中，UDCA未表现出FXR激动或拮抗活性。综合这些结果，我们推断，给予UDCA后肝脏胆汁酸组成的上述变化可能主要通过降低法尼酯X受体拮抗剂β-MCA的含量，导致肝脏中FXR活性相对增加，这提示了UDCA抑制小鼠肝脏脂肪生成并降低脂质含量的一种机制。
