Seminar

Genetic disorders of biliary transport systems.

LUIS ALVAREZ, PhD

One of the main functions of the liver is the formation of bile and bile flow maintenance, which allows the biotransformation and excretion of numerous endogenous and exogenous substances and the intestinal absorption of cholesterol and fat soluble vitamins. Bile secretion is an osmotic process that occurs in the bile canaliculi, small spaces formed between the apical (canalicular) membrane of adjacent hepatocytes. Most solutes that form bile (phospholipids, bile salts, cholesterol, organic anions, etc.) are secreted by a number of transporters located in the canalicular membrane of the hepatocyte in a process dependent on ATP hydrolysis. Mutations in some of these proteins give rise to certain forms of cholestasis (a term that refers to the absence or reduction of bile flow), which have a recessive inheritance pattern and manifest in the neonatal period. The entities that have a poorer prognosis are due to mutations in the bile salt export pump (BSEP), a flippase for phosphatidylcholine, MDR3, and a P-type ATPase, called ATP8B1, involved in translocation of aminophospholipids from the outer to the inner leaflet of the plasma membrane bilayer. Liver disease in BSEP deficiency is ascribed to failed secretion and intrahepatocytic accumulation of toxic bile salts. Mutation in MDR3 leads to a marked reduction of phosphatidylcholine in bile, which precludes the neutralization of detergent bile salts and results in bile canaliculi and biliary epithelium injuries. ATP8B1 dysfunction seems to give rise to severe liver disease by downregulating Farnesoid X receptor (FXR), a bile acid-sensing transcription factor that controls bile salt homeostasis.