Hepatocanalicular Transport Defects: Pathophysiologic Mechanisms of Rare Diseases  Ronald P.J. Oude Elferink, Coen C. Paulusma, Albert K. Groen  Gastroenterology  Volume 130, Issue 3, Pages 908-925 (March 2006) DOI: 10.1053/j.gastro.2005.08.052 Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 1 Inherited diseases associated with mutations in canalicular transporter genes. The figure gives the name of a canalicular transporter gene in bold and the trivial name of its gene product between parentheses. The second line indicates its function and the third line indicates in bold the corresponding disease. Gastroenterology 2006 130, 908-925DOI: (10.1053/j.gastro.2005.08.052) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 2 The different types of lipid translocators in the canalicular membrane of the hepatocyte. Whereas MDR3 P-glycoprotein (ABCB4) and ABCG5/G8 mediate outward translocation (“flopping”) of phosphatidylcholine (PC) and cholesterol, respectively, FIC1 (ATP8B1) is assumed to mediate inward translocation (“flipping”) of aminophospholipids (PS and phosphatidylethanolamine) and possibly also phosphatidylcholine (PC). Gastroenterology 2006 130, 908-925DOI: (10.1053/j.gastro.2005.08.052) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 3 Phase diagram for the (co-)existence of the liquid-disordered (ld), the liquid-ordered (lo), and solid-ordered (so) phases in membranes with various relative compositions of POPC, P-SM, and cholesterol. Abbreviations: POPC, phosphatidylcholine (containing 1 palimitic and 1 oleic fatty acyl chain); P-SM, sphingomyelin with a palmitic acyl chain. The solid square represents the composition of the basolateral membrane and the solid circle the composition of the canalicular membrane as purified and analyzed by Nibbering et al.110 The arrow indicates the direction in which the canalicular membrane composition approximately changes if corrected for contaminating other membranes (mainly basolateral membranes and ER membranes). The upper (faint) part of the diagram represents relative cholesterol contents (>66%) at which cholesterol is not soluble in the membrane. The figure was modified from Simons and Vaz107 and de Almeida et al.109 Gastroenterology 2006 130, 908-925DOI: (10.1053/j.gastro.2005.08.052) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 4 The relation between biliary bile salt and cholesterol excretion in wild type mice and in mice with a disruption of the Abcg8 gene. The animals were infused with increasing amounts of taurocholate. Data from Kosters et al.116 Gastroenterology 2006 130, 908-925DOI: (10.1053/j.gastro.2005.08.052) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 5 A possible mechanism for the sequence of steps in biliary lipid excretion. Bile salts (green) are pumped into the canalicular lumen by BSEP (ABCB11) and reach sufficiently high concentrations to form micelles. Phospholipid molecules (mainly phosphatidylcholine; red headgroup) are translocated by MDR3 (ABCB4) and the bile salt micelles either accept these molecules directly from the floppase or extract them from the membrane. ABCG5/G8 translocates cholesterol (light blue ovals) across the membrane but, more importantly, also lifts the molecules from the bilayer so that they can be accepted by mixed micelles of bile salt and PC, which are good cholesterol solubilizers. Please note that independently of ABCG5/G8 function cholesterol reaches the outer leaflet by spontaneous flip-flop. The outer leaflet consists mainly of sphingomyelin (blue headgroups) and cholesterol. Any aminophospholipid (white headgroups), that reaches the outer leaflet is translocated back by FIC1 (ATP8B1), thereby keeping the outer leaflet in its detergent-resistant state. Modified from Small.119 Gastroenterology 2006 130, 908-925DOI: (10.1053/j.gastro.2005.08.052) Copyright © 2006 American Gastroenterological Association Terms and Conditions