Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Hepatology. 2020 Dec;72(6):2165-2181. doi: 10.1002/hep.31239. Epub 2020 Nov 13.
Hepatic crisis is an emergent complication affecting patients with sickle cell disease (SCD); however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock-in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD-associated hepato-pathophysiology applying our recently developed quantitative liver intravital imaging, RNA sequence analysis, and biochemical approaches.
SCD mice manifested sinusoidal ischemia, progressive hepatomegaly, liver injury, hyperbilirubinemia, and increased ductular reaction under basal conditions. Nuclear factor kappa B (NF-κB) activation in the liver of SCD mice inhibited farnesoid X receptor (FXR) signaling and its downstream targets, leading to loss of canalicular bile transport and altered bile acid pool. Intravital imaging revealed impaired bile secretion into the bile canaliculi, which was secondary to loss of canalicular bile transport and bile acid metabolism, leading to intrahepatic bile accumulation in SCD mouse liver. Blocking NF-κB activation rescued FXR signaling and partially ameliorated liver injury and sinusoidal ischemia in SCD mice.
These findings identify that NF-κB/FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of therapies to treat sickle cell hepatic crisis.
肝危象是影响镰状细胞病（SCD）患者的一种紧急并发症；然而，镰状细胞肝胆损伤的分子机制仍知之甚少。我们使用 SCD 的基因敲入人源化小鼠模型和 SCD 患者的血液，应用我们最近开发的定量肝活体成像、RNA 序列分析和生化方法，试图从机制上描述 SCD 相关的肝病理生理学。
SCD 小鼠在基础条件下表现出窦状隙缺血、进行性肝肿大、肝损伤、高胆红素血症和胆管反应增加。SCD 小鼠肝脏中核因子 kappa B（NF-κB）的激活抑制法尼醇 X 受体（FXR）信号及其下游靶标，导致胆小管胆汁转运和胆汁酸池改变而丧失胆盐转运。活体成像显示胆汁分泌进入胆小管受损，这是由于胆小管胆汁转运和胆汁酸代谢丧失导致肝内胆汁积聚。阻断 NF-κB 激活可挽救 FXR 信号，并部分改善 SCD 小鼠的肝损伤和窦状隙缺血。
这些发现表明，NF-κB/FXR 依赖性胆汁分泌受损促进肝内胆汁积聚，从而导致 SCD 的肝胆损伤。对这些过程的深入了解可能有助于开发治疗镰状细胞肝危象的疗法。
