Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery,University Hospital Zurich, Zurich, Switzerland.
Hepatology. 2012 Jul;56(1):209-18. doi: 10.1002/hep.25626. Epub 2012 Jun 5.
Obstructive cholestasis induces liver injury, postoperative complications, and mortality after surgery. Adaptive control of cholestasis, including bile salt homeostasis, is necessary for recovery and survival. Peripheral serotonin is a cytoprotective neurotransmitter also associated with liver regeneration. The effect of serotonin on cholestatic liver injury is not known. Therefore, we tested whether serotonin affects the severity of cholestatic liver injury. We induced cholestasis by ligation of the bile duct (BDL) in either wild-type (WT) mice or mice lacking peripheral serotonin (Tph1(-/-) and immune thrombocytopenic [ITP] mice). Liver injury was assessed by the levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and tissue necrosis. Bile salt-regulating genes were measured by quantitative polymerase chain reaction and confirmed by western blotting and immunohistochemistry. Tph1(-/-) mice displayed higher levels of plasma AST, ALT, bile salts, and hepatic necrosis after 3 days of BDL than WT mice. Likewise, liver injury was disproportional in ITP mice. Moreover, severe cholestatic complications and mortality after prolonged BDL were increased in Tph1(-/-) mice. Despite the elevation in toxic bile salts, expression of genes involved in bile salt homeostasis and detoxification were not affected in Tph1(-/-) livers. In contrast, the bile salt reabsorption transporters Ostα and Ostβ were up-regulated in the kidneys of Tph1(-/-) mice, along with a decrease in urinary bile salt excretion. Serotonin reloading of Tph1(-/-) mice reversed this phenotype, resulting in a reduction of circulating bile salts and liver injury.
We propose a physiological function of serotonin is to ameliorate liver injury and stabilize the bile salt pool through adaptation of renal transporters in cholestasis.
阻塞性胆汁淤积会导致肝损伤、术后并发症和术后死亡率。胆汁淤积的适应性控制，包括胆汁盐的动态平衡，对于恢复和生存是必要的。外周血清素是一种具有细胞保护作用的神经递质，也与肝再生有关。血清素对胆汁淤积性肝损伤的影响尚不清楚。因此，我们测试了血清素是否会影响胆汁淤积性肝损伤的严重程度。我们通过结扎胆管（BDL）在野生型（WT）小鼠或缺乏外周血清素的小鼠（Tph1（-/-）和免疫性血小板减少症[ITP]小鼠）中诱导胆汁淤积。通过血浆天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和组织坏死来评估肝损伤。通过定量聚合酶链反应测量胆汁盐调节基因，并通过 Western 印迹和免疫组织化学进行证实。与 WT 小鼠相比，Tph1（-/-）小鼠在 BDL 后 3 天显示出更高的血浆 AST、ALT、胆汁盐和肝坏死水平。同样，ITP 小鼠的肝损伤不成比例。此外，Tph1（-/-）小鼠在延长 BDL 后出现严重的胆汁淤积并发症和死亡率增加。尽管有毒胆汁盐水平升高，但 Tph1（-/-）肝脏中参与胆汁盐动态平衡和解毒的基因表达没有受到影响。相反，Tph1（-/-）小鼠的肾脏中胆汁盐重吸收转运体 Ostα和 Ostβ上调，同时尿液胆汁盐排泄减少。Tph1（-/-）小鼠的血清素再加载逆转了这种表型，导致循环胆汁盐减少和肝损伤减轻。
我们提出血清素的生理功能是通过在胆汁淤积时适应肾脏转运体来改善肝损伤和稳定胆汁盐池。
