indicate that the biliary secretion rates of APF and of Anionic polypeptide fraction (APF) is a phospholipidphospholipids/cholesterol are not coupled and, thereand calcium-binding apoprotein present in animal and fore, do not support a direct physiological role of APF human bile, predominantly associated with cholesterolsecretion in biliary lipid secretion. APF secretion into phospholipid vesicles. In bile, the protein may play a bile may, at least partially, be controlled by biliary bile physiological role in preventing precipitation of calcium acid secretion. (HEPATOLOGY 1997;25:38-47.) salts. APF has also been suggested to be of regulatory importance in the process of biliary lipid secretion. The aim of the present study was to investigate whether the Anionic polypeptide fraction (APF) is a phospholipid-and secretion rates of APF and that of biliary lipids are coucalcium-binding apoprotein present in animal and human pled, which would support a physiological role of APF bile, which is predominantly associated with cholesterolin biliary lipid secretion. Biliary secretion rates of bile phospholipid vesicles. APF was originally described as part acids, phospholipids, and cholesterol were experimenof a biliary lipoprotein complex, present in human bile. 1 Pubtally modulated in three different rat models. Secretion lished data indicate that antibodies raised against APF crossrates of APF were compared with that of bile acids, lipreact with calcium-binding protein, which was isolated from ids, and with that of two other biliary proteins, the lysocholesterol and pigment gallstones. In human cholesterol somal protein b-glucuronidase and apolipoprotein A-I gallstones, APF is associated with the pigments at the inter- (apo A-I). Model 1: diurnal variation in bile formation faces of mucine and pigment. These observations have led during chronic bile diversion; model 2: specific inhibito the hypothesis that APF/calcium-binding protein may be tion of biliary phospholipid and cholesterol, but not of involved in the pathogenesis of cholesterol and/or pigment bile acid secretion by infusion of the organic anion, sulgallstone disease. Apart from the hypothesized role in gallfated lithocholyltaurine; model 3: acute interruption of stone formation, APF has been suggested to be involved in the enterohepatic circulation in unanesthetized rats. biliary lipid secretion under physiological circumstances. [8][9][10][12][13] The diurnal variation in bile formation involved a paral-The preferential association of APF with biliary lipid vesicles lel increase of the biliary secretion rates of bile acids and its amphipathic character could be in agreement with a (/56 { 7%, mean { SD), phospholipids (/53 { 29%), choproposed physiological role for APF in biliary lipid secretion. lesterol (/73 { 54%), and APF (/72 { 86%) during the Furthermore, the involvement of APF in intrahepatocytic tarnight phase of the cycle. Infusion of sulfated lithocholylgeting of plasma-derived lipids was suggested by experiments taurine inhibited biliary phospholipid and cholesterol in rats injected with liposomes with or without APF. 10 Comsecretion (078 { 15%, and 054 { 25%, respectively), but pared with cholesterol from control liposomes, cholesterol did not affect biliary bile acid or APF secretion rate (019 from liposomes including APF disappeared more rapidly from { 14%, and /12 { 107%, respectively). Within 4 hours the plasma after intravenous injection, could be recovered for after interruption of the enterohepatic circulation, bile a much higher percentage in the liver, was secreted into the secretion rates for bile acids (092 { 3%), phospholipids bile in a later stage, and was less efficiently metabolized into (074 { 13%), cholesterol (064 { 8%), and APF (058 { 24%) bile acids. 10 The differences in the metabolic fate of liposomerapidly declined to a new steady-state level. Correlation derived cholesterol after injection of APF-containing or conanalysis using the data from the three experimental trol liposomes suggested the involvement of APF in the regumodels indicated that the biliary secretion rate of APF lation of hepatocytic uptake, the intracellular distribution, was independent from that of phospholipids, cholesand the partitioning between plasma and bile of unesterified terol, b-glucuronidase, and, presumably, apolipoprotein cholesterol. 10 The involvement of proteins in the process of A-I, and positively correlated to bile acid secretion rate bile acid-induced lipid secretion has recently been sugand bile flow. The data from three experimental models gested. 14, Until now, the importance of one protein for bile acid-induced biliary lipid secretion has been demonstrated beyond reasonable doubt, i.e., that of the mdr2 gene prod-Abbreviations: APF, anionic polypeptide fraction; apo A-I, apolipoprotein A-I; STLC, uct. 16 The mdr2 gene product may function as a phosphosulfated lithocholyltaurine.