Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
PLoS One. 2022 Jul 12;17(7):e0271308. doi: 10.1371/journal.pone.0271308. eCollection 2022.
Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.
Cyp2a12-/-Cyp2c70-/- 双敲除 (DKO) 小鼠具有与人相似的疏水性胆汁酸 (BA) 组成，并表现出生育能力降低和肝损伤。熊去氧胆酸 (UDCA) 是一种亲水性和细胞保护型 BA，用于治疗人类的各种肝损伤。本研究探讨了口服 UDCA 对 DKO 小鼠生育能力和肝损伤的影响。UDCA 治疗可预防怀孕 DKO 小鼠的异常分娩（流产和早产），推测是通过增加血清 BA 的亲水性来实现的。UDCA 还可预防 6 周龄 DKO 小鼠的肝损伤，但在接受 UDCA 治疗的 20 周龄雌性而非雄性 DKO 小鼠中出现了肝损伤。在 20 周龄雄性 UDCA 处理的 DKO 小鼠中，血清、肝脏和胆汁中的结合型加非结合型 UDCA 比例分别占总 BA 的 71%、64%和 71%。相比之下，血清、肝脏和胆汁中的结合型加非结合型 UDCA 比例分别占雌性总 BA 的 56%、34%和 58%。UDCA 比例在雌性肝脏中相当低，由高度疏水性胆酸 (LCA) 补偿。因此，UDCA 治疗可显著降低雄性肝脏中 BA 的疏水性指数，但对雌性肝脏没有影响。这似乎就是为什么 UDCA 治疗会导致 20 周龄雌性小鼠的肝损伤。为了探究雌性肝脏中 LCA 积累的原因，我们评估了 CYP3A11 和 SULT2A1 的肝活性，这两种酶可将 LCAs 代谢为更亲水的 BAs。然而，没有证据表明雌性的这两种酶活性低于雄性。由于雌性小鼠的 BA 池比雄性大，因此 LCAs 对肝脏胆汁盐输出泵 (BSEP) 的过度加载可能是延长 UDCA 治疗后雌性 DKO 小鼠肝脏中 LCAs 积累的原因。我们的研究结果表明，UDCA 给药改善 DKO 小鼠 BA 的疏水性是性别、年龄和器官依赖性的。
