摘要

UDP-glucuronosyltransferase (UGT) 1A1 is the only transferase capable of conjugating serum bilirubin. However, temporal delay in the development of theUGT1A1型gene leads to an accumulation of serum bilirubin in newborn children. Neonatal humanizedUGT1(拥抱1)小鼠的血清总胆红素（TSB）积累严重，通过口服灌胃给予obeticholic acid（OCA），一种有效的FXR激动剂。OCA治疗可显著降低TSB水平。UGT1A1表达分析证实OCA诱导肠道而非肝脏UGT1A1。有趣的是，Cyp2b10, a target gene of the nuclear receptor CAR, was also induced by OCA in intestinal tissue. In neonatalhUGT1/车^−/−mice, OCA was unable to induce CYP2B10 and UGT1A1, confirming that CAR and not FXR is involved in the induction of intestinal UGT1A1. However, OCA did induce FXR target genes, such asShp在肠道和肝脏中都有Fgf15in intestinal tissue. Circulating FGF15 activates hepatic FXR and, together with hepaticShp, blocksCyp7a1和Cyp7b1gene expression, key enzymes in bile acid metabolism. Importantly, the administration of OCA in neonatal拥抱1mice accelerates intestinal epithelial cell maturation, which directly impacts on induction of theUGT1A1型基因和减少TSB的水平。加速intestinal maturation is directly controlled by CAR, since induction of enterocyte marker genes sucrase-isomaltase, alkaline phosphatase 3, and keratin 20 by OCA does not occur inhUGT1/车^−/−mice. Thus, new findings link an important role for CAR in intestinal UGT1A1 induction and its role in the intestinal maturation pathway.