Fig. 4.

Overview of hepatocyte adaptation to cholestatic injury. Hepatocytes can adapt to increased cholestatic injury seen due to enhanced bile acids in the liver. Several key nuclear receptors sense an increased bile acid pool and begin inhibiting de novo synthesis in an attempt to decrease total bile acid content. They also reduce bile acid hydrophobicity through increased conjugation, increase phospholipid secretion into bile to decrease toxicity, reduce apical transport of bile acids if there is obstruction or limited biliary canalicular or ductal flow, and enhance basolateral efflux of bile acids into sinusoidal blood to promote their exit from the liver. Bile acids can also directly or indirectly result in YAP1 activation through changing the mechanical tension in the bile canalicular wall and altering Hippo pathway activity. Hepatocyte can, thus, undergo metabolic reprogramming of bile acids and at the same time decrease its general synthetic and metabolic functions while it turns on proliferative program to maintain mass, as was seen in an extreme case of complete intrahepatic biliary tree absence due to hepatoblast-specific YAP1 deletion in mice.