Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (A.A.W., E.M., X.Y., S.C., R.H.T.) and Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (L.W.E.v.d.S., J.W.J.).
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (A.A.W., E.M., X.Y., S.C., R.H.T.) and Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (L.W.E.v.d.S., J.W.J.)
Drug Metab Dispos. 2021 Jan;49(1):12-19. doi: 10.1124/dmd.120.000240. Epub 2020 Nov 5.
UDP-glucuronosyltransferase (UGT) 1A1 is the only transferase capable of conjugating serum bilirubin. However, temporal delay in the development of the gene leads to an accumulation of serum bilirubin in newborn children. Neonatal humanized () mice, which accumulate severe levels of total serum bilirubin (TSB), were treated by oral gavage with obeticholic acid (OCA), a potent FXR agonist. OCA treatment led to dramatic reduction in TSB levels. Analysis of UGT1A1 expression confirmed that OCA induced intestinal and not hepatic UGT1A1. Interestingly, , a target gene of the nuclear receptor CAR, was also induced by OCA in intestinal tissue. In neonatal 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 as , in both intestines and liver with induction of in intestinal tissue. Circulating FGF15 activates hepatic FXR and, together with hepatic , blocks and gene expression, key enzymes in bile acid metabolism. Importantly, the administration of OCA in neonatal mice accelerates intestinal epithelial cell maturation, which directly impacts on induction of the gene and the reduction in TSB levels. Accelerated 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 in mice. Thus, new findings link an important role for CAR in intestinal UGT1A1 induction and its role in the intestinal maturation pathway. SIGNIFICANCE STATEMENT: Obeticholic acid (OCA) activates FXR target genes in both liver and intestinal tissues while inducing intestinal UGT1A1, which leads to the elimination of serum bilirubin in humanized mice. However, the induction of intestinal UGT1A1 and the elimination of bilirubin by OCA is driven entirely by activation of intestinal CAR and not FXR. The elimination of serum bilirubin is based on a CAR-dependent mechanism that facilitates the acceleration of intestinal epithelium cell differentiation, an event that underlies the induction of intestinal UGT1A1.
UDP-葡糖醛酸基转移酶 (UGT) 1A1 是唯一能够结合血清胆红素的转移酶。然而，该基因的发育存在时间延迟，导致新生儿血液中胆红素积累。新生的人源化 () 小鼠积累了严重的总血清胆红素 (TSB)，通过口服给予法尼醇 X 受体 (FXR) 激动剂奥贝胆酸 (OCA) 进行治疗。OCA 治疗导致 TSB 水平显著降低。UGT1A1 表达分析证实，OCA 诱导了肠道而非肝脏 UGT1A1。有趣的是，核受体 CAR 的靶基因也被 OCA 在肠道组织中诱导。在新生的 小鼠中，OCA 不能诱导 CYP2B10 和 UGT1A1，这证实了 CAR 而不是 FXR 参与了肠道 UGT1A1 的诱导。然而，OCA 确实诱导了 FXR 靶基因，如 ，在肠道和肝脏中，并诱导了 在肠道组织中。循环 FGF15 激活肝 FXR，并与肝 一起阻断 和 基因表达，这是胆汁酸代谢的关键酶。重要的是，在新生的 小鼠中给予 OCA 可加速肠道上皮细胞成熟，这直接影响 基因的诱导和 TSB 水平的降低。肠道成熟的加速直接受到 CAR 的控制，因为 OCA 不会诱导 小鼠肠细胞标记基因蔗糖酶异麦芽糖酶、碱性磷酸酶 3 和角蛋白 20 的表达。因此，新发现将 CAR 在肠道 UGT1A1 诱导中的重要作用及其在肠道成熟途径中的作用联系起来。意义陈述：奥贝胆酸 (OCA) 激活肝和肠道组织中的 FXR 靶基因，同时诱导人源化 小鼠的肠道 UGT1A1，从而消除血清胆红素。然而，OCA 诱导肠道 UGT1A1 和消除胆红素完全由肠道 CAR 的激活驱动，而不是 FXR。血清胆红素的消除基于一种 CAR 依赖性机制，该机制促进了肠道上皮细胞分化的加速，这是诱导肠道 UGT1A1 的基础。
