Additionally, FXR selleck chemicals indirectly represses the
expression of bile acid import [Na+-taurocholate cotransporting polypeptide (NTCP)7] and synthesis genes [cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B1 (CYP8B1)8] through the induction of a transcriptional repressor, small heterodimer partner (SHP), in the liver8 and a signaling hormone, fibroblast growth factor 19 (FGF19)/Fgf15, in the intestine.9 FXR therefore plays a central role in preventing the toxic accumulation of bile acids in the liver. Intrahepatic cholestasis of pregnancy (ICP) is characterized by raised serum bile acid levels and abnormal liver function tests. The disease is associated with fetal distress, spontaneous preterm delivery, and unexplained
intrauterine death.10 We have identified genetic variants of FXR, BSEP, and MDR3 that contribute to the etiology of ICP.11-13 However, it is currently not known Seliciclib how pregnancy unmasks cholestatic disease in these genetically predisposed but otherwise normal individuals. Importantly, gestation itself may be a state of impaired bile acid homeostasis because up to 40% of women develop asymptomatic hypercholemia of pregnancy,14 and an increase in the total bile acid pool has also been reported.15 As such, the mechanisms that affect bile acid homeostasis during normal pregnancy may also be relevant to the etiology of ICP. For a number of reasons, estrogens are thought to contribute to the etiology of ICP.16
First, the disease usually develops in the third trimester of pregnancy when concentrations of estrogens are highest. Second, twin pregnancies have both a higher incidence of ICP and a more pronounced rise in estradiol concentrations.17 Third, ICP patients can present with cholestasis outside of pregnancy when they are taking oral contraceptives containing 17α-ethinylestradiol.18 High doses of estradiol and its metabolites also cause cholestasis in rodents,19 and mice lacking ER are resistant to these effects.20 Taken together, these findings imply 上海皓元 that estrogens could dysregulate bile acid homeostasis in normal pregnant women and trigger cholestatic disease in genetically predisposed individuals. However, liver biopsy is not clinically indicated in the majority of ICP cases, so data on the response of the human liver to pregnancy and ICP are limited. In this report, we investigate whether bile homeostasis is dysregulated in pregnant mice and whether this is due to impairment of Fxr function. We show that hepatic bile acids are raised in pregnant mice and that liver gene expression is procholestatic and resembles a state of Fxr inactivation. We provide in vivo and in vitro evidence showing that estrogen or its metabolites may be the underlying cause of Fxr dysfunction.