Mechanism of bile acid-induced HCO3−-rich hypercholeresis An analysis based on quantitative acid-base chemistry (original) (raw)
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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.
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.
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. ...
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-induced liver toxicity: Relation to the hydrophobic-hydrophilic balance of bile acids
Medical Hypotheses, 1986
Hypertransaminasemia is a frequent side effect during chenodeoxycholic administration for gallstone dissolution. Evidence suggests that this effect is not mediated by lithocholic acid, the intestinal metabolite of chenodeoxycholic acid, but that toxicity is due to the chenodeoxychol~c acid itself. In vitro cytotoxicity of bile salts is positively proportional to their detergent effect, which is, on the other hand, related to their hydrophobic-hydrophilic balance. We hypothesize that in vivo also liver injury can occur when the liver is perfused by an high proportion of strongly detergent bile salts. The more detergent bile salts are unconjugated or glycine conjugated, while the lesser are taurine conjugated and sulfated. Within each class the following order of decreasing detergent power can be indicated: lithocholic) deoxycholic) chenodeoxycholic > cholic > ursodeoxycholic acid. Besides chronic exogenous administration of chenodeoxycholic or deoxycholic acids, conditions in which the liver is perfused by an high mass of highly detergent bile salts are those characterized by an enhanced intestinal biodegradation of bile salts. These conditions, which are common features of some chronic inflammatory bowel diseases, are frequently associated with liver damage. On the other hand, a normally detergent bile salt pool can become hepatotoxic for liver cells which have already been injured. In this respect, as already reported for increased sulfation, the increased proportion of taurine conjugates and the reduced formation of deoxycholic acid in liver cirrhosis can be regarded as protective mechanisms. Liver toxicity induced by bile salts' detergency can be prevented by favouring tauroconjugation or reducing the intestinal degradation of bile salts or by administering poorly detergent bile salts.
Journal of Gastroenterology and Hepatology, 1996
Hepatic sinusoidal uptake of bile acids is mediated by defined carrier proteins against unfavourable concentration and electrical gradients. Putative carrier proteins have been identified using bile acid photoaffinity labels and more recently using immunological probes, such as monoclonal antibodies. At the sinusoidal domain, proteins with molecular weights of 49 and 54kDa have been shown to be carriers for bile acid transport. The 49 kDa protein has been associated with the Na'dependent uptake of conjugated bile acids, while the 54 kDa carrier has been involved in the Na+independent bile acid uptake process. Within the hepatocyte, cytosolic proteins, such as the glutathione S-transferase (also designated the Y protein), the Y binders and the fatty acid binding proteins, are able to bind bile acids and possibly facilitate their movement to the canalicular domain. At the canalicular domain a 100 kDa carrier protein has been isolated and it has been shown by several laboratories that this particular protein is concerned with canalicular bile acid transport. The system is ATP-dependent and follows Michaelis-Menten kinetics. Interference with bile acid transport has been demonstrated by several chemicals. The mechanisms by which these chemicals inhibit bile acid transport may explain the apparent cholestatic properties observed in patients and experimental animals treated with these agents. Several studies have shown that Na 'X+-ATPase activity is markedly decreased in cholestasis induced by ethinyloestradiol, taurolithocholate and chlorpromazine. However, other types of interference have been described and the cholestatic effects may be the result of several mechanisms. Cholestasis is associated with several adaptive changes that may be responsible for the accumulation of bile acids and other cholephilic compounds in the blood of these patients. It may be speculated that the nature of these changes is to protect liver parenchymal cells from an accumulation of bile acids to toxic levels. However, more detailed quantitative experiments are necessary to answer questions with regard to the significance of these changes and the effect of various hepatobiliary disorders in modifying these mechanisms. It is expected that the mechanisms by which bile acid transport is regulated and efforts to understand the molecular basis for these processes will be among the areas of future research.
Altered bile acid metabolism in primary biliary cirrhosis
Digestive Diseases and Sciences, 1981
Selected aspects of bile acid metabolism were assessed in six women with primary biliary cirrhosis and varying degrees of cholestasis. Urinary bile acid excretion was markedly increased and correlated highly with serum levels. In three patients in whom urinary bile acids were separated by chromatography, the majority of urinary bile acids were monosulfated (34%, 42%, 32%) or polysulfated and~or glucuronidated (30%, 20%, 38%). The monosulfates of chenodeoxycholic acid were conjugated at either the 3 position (67%, 68%, 73%) or the 7 position (33%, 32%, 27%); similarly, the monosulfates of cholic cicid were conjugated at the 3 position (65%, 58%, 68%) or the 7position (35%, 42%, 32%). The position of sulfation was not markedly influenced by the mode of amidation with glycine or taurine. Chenodeoxycholic exchangeable pool size, turnover rate, and synthesis were measured by isotope dilution and found to be well within normal limits, despite the cholestasis. The fraction of chenodeoxycholic acid synthesis excreted in urine ranged from 9 to 48%; 4-38% of chenodeoxycholic acid synthesis was sulfated. These data indicate that the major abnormalities in bile acid metabolism in patients with cholestasis secondary to primary biliary cirrhosis are formdtion of sulfated bile acids in greatly increased amounts, elevation of blood levels of primary bile acids, and a shift to renal excretion aS a major mechanism for bile acid elimination. Chenodeoxycholic acid Synthesis continues at its usual rate despite cholestasis. Whether these changes, including the formation of 7-monosulfated bile acids, occur in other forms of cholestasis and whether either" the persistance of unchanged chenodeoxycholic acid synthesis or the formation of such novel conjugates has any pathophysiological significance remain to be investigated.
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.