Sinal C J, Tohkin M, Miyata M, Ward J M, Lambert G, Gonzalez F J
Laboratory of Metabolism, Division of Basic Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cell. 2000 Sep 15;102(6):731-44. doi: 10.1016/s0092-8674(00)00062-3.
Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
缺乏核胆汁酸受体FXR/BAR的小鼠发育正常，外观与野生型同窝小鼠无异。FXR/BAR基因敲除小鼠与野生型小鼠的区别在于血清胆汁酸、胆固醇和甘油三酯升高，肝脏胆固醇和甘油三酯增加，以及具有促动脉粥样硬化的血清脂蛋白谱。由于主要肝小管胆汁酸转运蛋白的表达降低，FXR/BAR基因敲除小鼠的胆汁酸池也减少，粪便胆汁酸排泄降低。在FXR/BAR基因敲除小鼠中，分别未出现胆汁酸对胆固醇7α-羟化酶和回肠胆汁酸结合蛋白的抑制和诱导作用，从而确立了FXR/BAR在体内对这些基因表达的调节作用。这些数据表明，FXR/BAR作为细胞内胆汁酸传感器，对胆汁酸和脂质稳态至关重要。
