Quantitative relationship between bile acid structure and biliary lipid secretion in rats (original) (raw)
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Biochimica Et Biophysica Acta (bba) - Lipids and Lipid Metabolism, 1994
Earlier studies suggested that the secretory rate maximum (SRm) of bile acid and the cholestasis which occurs after the SRm is reached may be determined by the hepatic or extrahepatic biliary phospholipid pool. We therefore investigated whether bile formation and the bile acid SRm could be influenced by feeding a diet enriched in phospholipids. Male rats were fed phospholipid (PLD) or triacylglycerol (TgD) -enriched diet for 3 days, and bile formation as well as biliary lipid output were measured on the 4th day. In other similarly fed groups, cholic acid was infused in stepwise increasing doses to determine the effect of PLD on the SRm of cholic acid. The plasma lipid levels were significantly lower in PLD and TgD diets compared to basal diet. But, while the levels of total cholesterol (CH), HDL-CH, and phospholipid (PH) were not significantly altered by PLD compared to TgD, the triacylglycerol levels were markedly increased by PLD. In the liver of PLD fed rats, triacylglycerol and CH ester contents decreased by 39 and 62%, respectively, while free CH and PH contents were not significantly changed. The PLD significantly augmented spontaneous bile flow, bile acid, PH and CH secretion rates compared to TgD diet (65, 124, 164 and 654%, respectively). The enhanced biliary secretory function was associated with an increase in pericanalicular vacuoles and diverticuli in centrilobular hepatocytes. Compared to TgD fed rats, PLD rats showed a 2-fold decrease in the ratio of cholic acid/chenodeoxycholic acid in bile and a significant decrease in the % contribution of taurine conjugated BA. The PH fatty acids in bile were similar in both groups except that in PLD group the % contribution of C18:2 was higher than in TgD group. No differences were found in plasma membrane CH/PH content or total fatty acid composition. During bile acid infusion, the SRm and the total cholic acid secreted were significantly higher in the PLD than in the TgD rats. Moreover, the cholestatic response observed after high bile acid dose was markedly reduced by PLD. The results show that short-term feeding of PLD induces changes in CH and bile acid metabolism which result in enhanced biliary output of CH and PH. The enhanced pool of biliary lipid may protect plasma membranes from the deleterious effects of high bile acid concentrations.
Digestive Diseases and Sciences, 1994
Taurohyodeoxycholic acid is a natural 6et-hydroxylated bile acid with an apparent hydrophilicity intermediate between those of tauroursodeoxycholic and taurocholic acids. We investigated in the rat the hepatobiliary metabolism, choleretic properties, and biliary maximum secretory rate (SRmax) of taurohyodeoxycholic in comparison with these two bile salts. Each compound was infused intravenously, at a rate increased in a stepwise manner from 100 to 300 nmol/min/100 g body wt, in bile salt-depleted bile fistula rats. The three bile salts appeared rapidly starting with the infusion and increased to represent more than 95% of the total bile salts. No apparent biliary metabolites were formed. All the bile salts caused a dose-dependent increase in bile flow and biliary lipid output. The absolute increase in bile flow was lower in rats infused with taurohyodeoxycholic acid, yet the volume of bile formed per nanomole of secreted bile salt was 13.8 nl for taurohyodeoxycholic, 6.4 nl for tauroursodeoxycholic acid, and 10.9 nl for taurocholic. The SRm~, , values were 1080, 3240, and 960 nmol/min/100 g, respectively. At all infusion rates, taurohyodeoxycholic acid caused a greater (P < 0.001) secretion of biliary lecithin compared to the other bile salts. There were no significant differences in the biliary secretion of cholesterol and proteins. Electron microscopy showed the recruitment of vesicles and lamellar bodies around and within bile canaliculi. In conclusion, taurohyodeoxycholic promotes a biliary lecithin secretion greater than expected from physicochemical predictions, representing a novel secretory property with potential pharmacological relevance.
Hepatology, 1997
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. 2,3 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. 4 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. 5-7 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. 8-13 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. 14,15 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. 15,16 The mdr2 gene product may function as a phosphosulfated lithocholyltaurine.
Hepatic uptake and biliary secretion of bile acids in the perfused rat liver
Pharmacological Research, 1992
Hepatic uptake and biliary secretion have been evaluated in the isolated perfused rat liver for cholic, chenodeoxycholic, ursodeoxycholic acid, both free and taurine-conjugated; the physicochemical properties of the bile acids have also been calculated and related to these experimental parameters. Cholic acid disappearance rate from the perfusate was the fastest, followed by that of ursodeoxycholic and chenodeoxycholic; it was also faster for taurine-conjugated bile acids than for their respective unconjugated forms. The recovery in bile was higher for conjugated than for unconjugated bile acids, and, among each class, was higher for cholic than for chenodeoxycholic and ursodeoxycholic. The hepatic uptake correlated negatively (r=-0.99) with the bile acid lipophilicity, while the biliary secretion correlated with the solubility of the molecules. These results show the effect of the physicochemical properties of BA on their hepatic handling, at the physiological concentration of BA in the portal blood.
INFLUENCE OF BILE ACIDS ON THE BILIARY TRANSPORT MAXIMUM OF PHENOLSULPHONPHTHALEIN IN THE RAT
Clinical and Experimental Pharmacology and Physiology, 1988
1. The effect of changes in bile acid secretion induced by cholestyramine treatment or taurocholate infusion on the biliary transport maximum (Tm) of phenolsulfonphthalein (PSP) was studied in Wistar rats. 2. Five hours after oral administration of cholestyramine (1.5 g/kg bodyweight) the biliary output of bile acids decreased to 51% and bile flow to 76% of control values. The percentage of conjugated and unconjugated PSP excreted into bile and the Tm of the dye were not significantly modified by cholestyramine pretreatment. 3. Administration of sodium taurocholate at increasing rates (60-480 nmol/100 g bodyweight per min) enhanced bile flow and the biliary output of bile acids in a linear dose-related fashion. The Tm of PSP increased progressively until a maximum of 29% above the control values was reached at a taurocholate dose of 240 nmol/100 g bodyweight per min). The enhancement corresponded mainly to the unconjugated dye, the excretion of conjugated PSP not being significantly modified by the infusion of the bile acid. 4. The results indicate that bile acids can influence to some extent biliary excretion of PSP in the rat, although this component is of minor importance at low bile acid secretory rates.
Ultracentrifugal isolation of vesicular carriers of biliary cholesterol in native human and rat bile
Hepatology, 1987
We have utilized ultracentrifugation of native bile-Metrizamide density gradients to isolate a vesicular transport system or biliary lipids in both man and rat. We identified vesicular structures by electron microscopy. Fresh bile specimens were obtained from bile fistula rats (unsaturated bile) and from patients 1 week after bile duct surgery (supersaturated bile). Metrizamide was dissolved in bile (33% w/v), and continuous density gradients were performed with undiluted bile (density limits = 1.020 to 1.300 gm per ml). The relative distribution of biliary cholesterol, phospholipid and bile salt was studied as a function of the density of the fractions. Approximately 50% of total rat biliary cholesterol and between 61 and 90% of human biliary cholesterol was concentrated in the lightest fractions of the gradients (density < 1.060 gm per ml). In contrast, less than 20% of bile salts was present in fractions with densities lower than 1.060 gm per ml. The highest amounts of bile salts and phospholipids of the bile-Metrizamide density gradients were found in the density range of 1.075 to 1.100 gm per ml in both human and rat bile. More than 80% of biliary proteins was found in fractions with densities < 1.075 gm per ml, and only 2% was found in the cholesterol-rich fraction with density < 1.060 gm per ml in both species. When bile salt concentration was raised in rat bile from 38 to 97 mM by adding taurocholate, the low density cholesterol-rich fraction almost disappeared. Electron microscopy of negatively stained preparations of the fractions with density < 1.060 gm per ml showed 40 to 120 nm vesicles, which were not apparent in the other fractions. Similar vesicles were demonstrated also in fresh rat bile and within the canaliculi after acute depletion of the bile salt pool (biliary bile salt concentration of 3.45 mM; total biliary lipid concentration of 0.25 gm%). The structure of these vesicles was shown in thin sections of liver specimens. They appeared as internal cavities surrounded by a single, continuous 6-nm-thick bilayer. These studies demonstrate that a high proportion of biliary cholesterol is transported in vesicles in human supersaturated native bile and that vesicular carriers are also responsible for the transport of a significant amount of biliary cholesterol in unsaturated rat bile. The presence of vesicles in unsaturated hepatic bile strongly supports the thesis that biliary lipids may be secreted as vesicles from the hepatocyte into the canaliculi.
World Journal of Gastroenterology, 2008
During the last decades the concept of bile secretion as merely a way to add detergent components to the intestinal mixture to facilitate fat digestion/absorption and to eliminate side products of heme metabolism has evolved considerably. In the series of mini-reviews that the World Journal of Gastroenterology is to publish in its section of "Highlight Topics", we will intend to give a brief but updated overview of our knowledge in this field. This introductory letter is intended to thank all scientists who have contributed to the development of this area of knowledge in gastroenterology.