Impaired bile secretion promotes hepatobiliary injury in Sickle Cell Disease.

Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. Here, we use intravital imaging to show that sinusoidal ischemia occurs in the liver of transgenic‐humanized SCD mice under basal condition. SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA‐sequence analysis identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, bile transport and cholesterol metabolism in the SCD mice liver. Immunohistochemical analysis confirmed inflammation, fibrosis and increased ductular reaction in SCD mice. Intravital imaging also revealed impaired bile secretion into the bile canaliculi, which was associated with loss of apical bile transporters and bile acid biosynthetic enzymes, hepatic bile accumulation, and activation of Farnesoid X receptor (FXR) and small heterodimer partner (Shp) in SCD mice liver. These findings are the first to identify that impaired bile acid synthesis and misexpression of bile transporters promote intrahepatic bile accumulation and impaired bile secretion, leading to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of new therapies to treat sickle cell hepatic crisis. Support or Funding Information TP‐S is funded by PLRC pilot and feasibility award and Community Liver Alliance Pilot Grant award.