New insights into the mechanism of bile acid?induced biliary lipid secretion*1 (original) (raw)
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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.
World Journal of Gastroenterology, 2008
The formation of bile depends on the structural and functional integrity of the bile-secretory apparatus and its impairment, in different situations, results in the syndrome of cholestasis. The structural bases that permit bile secretion as well as various aspects related with its composition and flow rate in physiological conditions will first be reviewed. Canalicular bile is produced by polarized hepatocytes that hold transporters in their basolateral (sinusoidal) and apical (canalicular) plasma membrane. This review summarizes recent data on the molecular determinants of this primary bile formation. The major function of the biliary tree is modification of canalicular bile by secretory and reabsorptive processes in bileduct epithelial cells (cholangiocytes) as bile passes through bile ducts. The mechanisms of fluid and solute transport in cholangiocytes will also be discussed. In contrast to hepatocytes where secretion is constant and poorly controlled, cholangiocyte secretion is regulated by hormones and nerves. A short section dedicated to these regulatory mechanisms of bile secretion has been included. The aim of this revision was to set the bases for other reviews in this series that will be devoted to specific issues related with biliary physiology and pathology.
Quantitative relationship between bile acid structure and biliary lipid secretion in rats
Journal of Pharmaceutical Sciences, 1988
A series of unconjugated and taurine conjugated bile acids (BAS) differing in water solubility (SW,), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 pmollminlkg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids
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.
Bile salt-associated electrolyte secretion
Experimental and Toxicologic Pathology, 1992
The mechanisms involved in bile salt-induced choleresis are poorly known. To give an insight in this physiological process, bile salt-associated electrolyte secretion was studied following relief of a short-term (2 h) biliary .obstruction in the rat, an experimental model that shows an important diminution of bile salt choleretic efficiency. For this purpose, biliary excretion of total bile salts and electrolytes (sodium, chloride and bicarbonate) were studied in such a model during taurocholate infusion at increasing rates. The results showed that bile flow, bile salt output and electrolyte secretion stimulated by taurocholate,administration were decreased in the rats that were subjected to biliary obstruction. Besides, the choleretic efficiency of the excreted bile salts, as estimated by the slope of the regression line of bile flow vs. bile salt output, was diminished by 46 % (p < 0.005). Multiple regression analysis of bile flow vs. bile salt and electrolyte outputs allowed to detect a selective diminution of the fraction of bile flow related to bile salt-associated electrolyte secretion ("secretory fraction" of the choleretic efficiency of bile salts) (3.2 ± 0.3 vs. 2.5 ± 0.2L1mol, p < 0.05) whereas the "osmotic fraction" of the choleretic efficiency of bile salts was not modified by the treatment (5. a ± 0.4 vs. 5.1 ± 0.3 Llmol, p> 0.05). Since both chloride and bicarbonate biliary concentrations in the volume of bile stimulated by taurocholate were reduced by 53 % and 52 % respectively, a role of these anions in the generation of bile salt-induced choleresis was suggested. Possible mechanisms involved in such a process and in its early impairment during cholestasis are discussed.
Bile Acids in Physiology, Pathology and Pharmacology
Current Drug Metabolism, 2015
Bile acids, synthesized by hepatocytes from cholesterol, are specific and quantitatively important organic components of bile, where they are the main driving force of the osmotic process that generates bile flow toward the canaliculus. The bile acid pool comprises a variety of species of amphipathic acidic steroids. They are not mere detergent molecules that play a key role in fat digestion and the intestinal absorption of hydrophobic compounds present in the intestinal lumen after meals, including liposoluble vitamins. They are now known to be involved in the regulation of multiple functions in liver cells, mainly hepatocytes and cholangiocytes, and also in extrahepatic tissues. The identification of nuclear receptors, such as farnesoid X receptor (FXR or NR1H4), and plasma membrane receptors, such as the G protein-coupled bile acid receptor (TGR5, GPBAR1 or MBAR), which are able to trigger specific and complex responses upon activation (with dissimilar sensitivities) by different bile acid molecular species and synthetic agonists, has opened a new and promising field of research whose implications extend to physiology, pathology and pharmacology. In addition, pharmacological development has taken advantage of advances in the understanding of the chemistry and biology of bile acids and the biological systems that interact with them, which in addition to the receptors include several families of transporters and export pumps, to generate novel bile acid derivatives aimed at treating different liver diseases, such as cholestasis, biliary diseases, metabolic disorders and cancer. This review is an update of the role of bile acids in health and disease.
Bile acid interactions with cholangiocytes
World Journal of Gastroenterology, 2006
Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostα-Ostβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogenactivated protein (MAP) kinase and extracellular signalregulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.
The Role of Bile Acids in the Human Body and in the Development of Diseases
Molecules
Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. ...