Section of Molecular Metabolism and Nutrition, Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Sci Rep. 2021 May 27;11(1):11107. doi: 10.1038/s41598-021-90687-5.
Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT11 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT11 mice with UDCA or OCA at postnatal days 10-14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.
新生儿高胆红素血症或黄疸可导致核黄疸，从而导致永久性神经损伤甚至死亡。传统的光疗并不能预防高胆红素血症或消除换血的需要。在这里，我们使用 hUGT11 人源化小鼠和 Ugt1a 缺陷 Gunn 大鼠研究了治疗性胆酸熊去氧胆酸（UDCA）和鹅去氧胆酸（OCA，6-α-乙基-CDCA），一种法尼醇 X 受体（FXR）激动剂，作为新生儿高胆红素血症预防治疗选择的潜力。在出生后第 10-14 天用 UDCA 或 OCA 治疗 hUGT11 小鼠可有效降低血浆（分别降低 82%和 62%）和大脑中的胆红素（分别降低 72%和 69%）。从机制上讲，我们的研究结果表明，这些作用是通过诱导肠道中 hUGT1A1 的蛋白水平来介导的，但不是在肝脏中。我们进一步证明，在 Ugt1a 缺陷 Gunn 大鼠中，UDCA 而非 OCA 可显著降低血浆胆红素，表明 UDCA 的至少部分降胆红素作用独立于 UGT1A1。最后，使用合成的非胆酸 FXR 激动剂 GW4064，我们表明其中一些作用是通过直接或间接激活 FXR 介导的。总之，我们的研究表明，治疗性胆酸 UDCA 和 OCA 可有效降低血浆和大脑中的胆红素，这突出了它们在治疗新生儿高胆红素血症中的潜力。
