Hepatobiliary Transport in Health and Disease

Abstract

Bile salts, cholesterol and phosphatidylcholine are secreted across the canalicular membrane of hepatocytes into bile by ATP-binding cassette (ABC) transporters. Secretion of bile salts by ABCB11 is essential for bile flow and for absorption of lipids and fat-soluble vitamins. ABCG5 and ABCG8 eliminate excess cholesterol and sterols from the body by secreting them into bile. There are two mechanisms to protect the canalicular membrane from solubilization by bile salts; ABCB4 secretes phosphatidylcholine into bile to form mixed micelles with bile salts, and ATP8B1 maintains the canalicular membrane in a liquid-ordered state. Three different forms of progressive familial intrahepatic cholestasis (PFIC) disorders, PFIC1, PFIC2 and PFIC3, are caused by mutations in ATP8B1, ABCB11 and ABCB4, respectively. Sitosterolemia is caused by mutations in ABCG5 and ABCG8. This article reviews the physiological roles of these canalicular transporters, and the pathophysiological processes and clinical features associated with their mutations. KeywordsATP-binding cassette transporter; bile; canalicular membrane; cholestasis; cholesterol; P4 ATPase; phospholipids Secretion of bile by the liverThe liver produces bile, which is essential for the elimination of endogenous compounds and xenobiotics from the body, for the emulsification of fat and for the intestinal absorption of lipids and fat-soluble vitamins. Bile is secreted into the canaliculi, which are small channels formed by the apical membranes of adjacent hepatocytes. Active secretion of organic solutes into the bile canaliculi by hepatocytes creates an osmotic gradient that causes water and electrolytes to flow from hepatocytes into the bile canaliculi. From the canaliculi, hepatic bile flows into the bile ducts, then through the bile ducts into the gallbladder. During fasting, bile is stored in the gallbladder, where water and electrolytes are absorbed and the organic solutes become more concentrated in gallbladder bile. During feeding, in response to stimulation by cholecystokinin and secretin, bile flows from the gallbladder into the small intestine [1,2].Transporters located at the canalicular membrane efflux endogenous compounds (bile salts, phospholipids, cholesterol and bilirubin) and xenobiotics (drugs, carcinogens and their Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Defects in ABCB11, ABCB4 and ATP8B1 cause progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of rare, autosomal recessive liver diseases of childhood. The estimated incidence is between 1:50,000 and 1:100,000 births [5]. Defects in either ABCG5 or ABCG8 cause an extremely rare autosomal recessive disease, sitosterolemia; only 80-100 cases have been report...