The molecular mechanisms controlling the tissue-specific expression of ASBT are not known. Expression is largely restricted to the ileum in mice, hamster, rats, and humans — Regulation of ASBT expression along the longitudinal axis of the intestine is not fully understood although recent studies showed that the transcription factor GATA4 is essential for this process. After injury or resection of distal small intestine, therapeutic options for restoring bile acid absorption have been limited as compensatory increases in ASBT expression appear to occur only in those remaining intestinal regions that natively expressed ASBT i.
However, the exciting finding that GATA4 is critical for establishing the functional gradient of bile acid absorption along the cephalocaudal axis of the small intestine reveals a novel opportunity for inducing proximal bile acid absorption by modulating the GATA4 pathway. The enterohepatic circulation efficiently conserves bile acids, thereby maintaining bile flow and adequate intraluminal bile acid concentrations for micellular solubilization and absorption of lipids. Considering its central role in the enterohepatic circulation, inherited defects or dysfunctional regulation of the ASBT may play a role in the pathogenesis or clinical presentation of a variety of gastrointestinal disorders.
For example, ASBT mutations were identified as a cause of primary bile acid malabsorption, a rare idiopathic disorder associated with interruption of the enterohepatic circulation of bile acids. Patients with primary bile acid malabsorption present with chronic diarrhea beginning in early infancy, steatorrhea, fat-soluble vitamin malabsorption, and reduced plasma cholesterol levels Although dysfunctional mutations were not found in the ASBT gene from patients with adult-onset forms of idiopathic bile acid malabsorption , aberrant regulation of the ASBT may still contribute to the phenotype in a subset of those patients Other disorders associated with intestinal bile acid malabsorption that could potentially involve the ASBT include hypertriglyceridemia , , idiopathic chronic diarrhea , chronic ileitis , gallstone disease , , postcholecystectomy diarrhea, Crohn's disease — , and irritable bowel syndrome Substrate, cytokines, hormones, and sterols all regulate transcription of the ASBT gene.
The regulation of ASBT expression by bile acids remains an area of controversy. Differences between experimental paradigms, methods for measuring ASBT protein or activity, species, and genetic background account for some of the discrepancies that have been observed , The dose and mode of delivery of bile acid is also an important consideration, as cell models do not recapitulate the in vivo dynamic flux of bile acids. In addition, bile acids are cytotoxic in high concentrations or under conditions of static exposure, and can activate a variety of signaling pathways 6. As such, it is important to try to distinguish between "basal" feedback regulation of ASBT expression and more complex responses to protect the cell from bile acid-induced injury.
Some of the earliest support for regulation of ASBT by bile acids was obtained from intestinal perfusion studies in the guinea pig; those studies showed that the ileal bile acid transport capacity was decreased after bile acid feeding and increased following the administration of a bile acid binding resin For humans, in vitro studies using Caco-2 cells or ileal biopsies have identified several different potential mechanisms for bile acid regulation of ASBT.
In vivo, several lines of evidence indirectly suggest that negative feedback regulation of intestinal bile acid transport is operational in humans, including the findings that retention of the bile acid analog 75 Se-homocholic acid-taurine is increased in primary biliary cirrhosis and intestinal ASBT expression is increased in patients with obstructive cholestasis However, these are pathophysiological states and clearly more needs to be done to understand how bile acids regulate their own active intestinal absorption under physiological conditions.
A new potential pathway for the bile acid-mediated repression of ASBT transcription has recently begun to emerge. In general agreement with that work, the addition of cholesterol to a cholic acid-containing diet appeared to downregulate ASBT expression and intestinal bile acid absorption by an FXR-independent mechanism Ileal inflammation is associated with bile acid malabsorption , and ASBT expression is decreased in animal models of ileitis and in ileal biopsies from patients with Crohn's disease In the setting of intestinal inflammation, c-fos is phosphorylated and translocates into the nucleus where binding of the downstream AP-1 element leads to transcriptional repression of ASBT expression Corticosteroids have had a long-standing use in the treatment of inflammatory bowel disease.
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In humans, exogenous corticosteroid Budesonide treatment increased ASBT expression in ileal biopsies, and this effect is mediated through glucorticorticoid receptor binding to specific response elements in the human ASBT promoter Thus, the beneficial effects of corticosteroids in inflammatory bowel disease may involve not only an effect on inflammatory cytokines but also a direct effect on ASBT expression In addition to transcriptional regulation, ASBT is regulated posttranscriptionally by modulating protein stability or transporter activity. The cholesterol-depleted cells exhibited no change in ASBT protein expression at the plasma membrane, suggesting that the decreased taurocholate uptake was due to reduced ASBT activity.
The proteins responsible for bile acid export across the basolateral membrane of the ileal enterocyte, cholangiocytes, and renal proximal tubule cell have only recently been identified. In contrast to apical transport, little was known regarding the mechanism and regulation of bile acid export across the basolateral membrane of these epithelia.
Several candidate ileal basolateral transporters had been partially characterized or implicated over the years, including a basolateral sodium-independent anion exchange activity , a bile acid photoprobe-labeled 54 kDa protein enriched in the ileal basolateral membrane fraction , an alternatively spliced form of the ASBT , and MRP3 ABCC3 However, none of these candidates fulfilled all the predicted criteria , and the identity of the basolateral bile acid transporter remained an important missing link in our understanding of the enterohepatic circulation.
Although the functional role of the individual subunits has not yet been determined, coexpression and assembly of both subunits into a complex is required for their trafficking to the plasma membrane and solute transport , These results were particularly perplexing because the whole body bile acid pool size was significantly decreased, a hallmark of intestinal bile acid malabsorption.
Roger Davis 75 , , Model for differential regulation of hepatic bile acid synthesis. Bile acids are secreted across the apical canalicular membrane into the bile canaliculus via the BSEP and undergo another round of enterohepatic cycling. A block in ileal brush border membrane uptake of bile acids results in downregulation of FXR target genes such as FGF The decreased FGF15 production and reduced return of bile acids to the liver leads to increased Cyp7a1 expression, increased hepatic conversion of cholesterol to bile acids, and reduced plasma cholesterol levels. This is the classical mechanism of action for the bile acid sequestrants.
In contract, a block in ileal basolateral bile acid export leads to increased bile acid retention and increased FXR-mediated activation of FGF15 expression. Despite reduced return of bile acids in the enterohepatic circulation, the ileal-derived FGF15 signals to repress hepatic Cyp7a1 expression and bile acid synthesis.
Whereas blocking apical bile acid uptake using bile acid sequestrants or ASBT inhibitors dramatically reduces the ileal expression of FGF15 and increases hepatic Cyp7a1 expression , a block in basolateral bile acid transport increases FGF15 expression and reduces hepatic bile acid synthesis. This combination of reduced return of bile acids in the enterohepatic circulation and reduced bile acid synthesis may have therapeutic benefit in various forms of cholestatic liver disease. Conversely, the reduction in bile acid synthesis associated with inhibition of basolateral transport could predispose to elevated plasma cholesterol levels in marked contrast to inhibition of apical ileal bile acid transport , Reno Vlahcevic in a study of gallstone patients that was published in Expression of both subunits is essential for function , and as such, the two subunit genes appear to be regulated coordinately.
The predominantly positive regulation would also ensure efficient export of bile acids thereby preventing cellular injury due to intracellular accumulation.
The binding of bile acids to plasma proteins reduces glomerular filtration and minimizes urinary excretion of bile acids. Even in patients with cholestatic liver disease in whom plasma bile acid concentrations are elevated, the h urinary excretion of nonsulfated bile acids is significantly less than the quantity that undergoes glomerular filtration — Subsequent studies have shown that bile acids in the glomerular filtrate are actively reabsorbed from the renal tubules by a sodium-dependent mechanism , and this process contributes to the rise in serum bile acid concentrations in patients with cholestatic liver disease.
As in the ileum, the renal proximal tubule epithelium expresses the ASBT as a salvage mechanism to conserve bile acids 55 , The overall pattern of bile acid membrane transporter expression appears to be similar for the ileal enterocyte and renal proximal tubule cells. In addition to the physiological implications, identification of the ASBT in kidney has therapeutic consequences.
Potent inhibitors of the ileal apical sodium bile acid transporter have been developed as potential therapies for hypercholesterolemia , — Because the same transporter is expressed in the kidney, these inhibitors could be used to block renal reclamation of bile acids and increase urinary bile acid output.
This would create a shunt for elimination of hepatotoxic bile acids; the predicted decrease in serum and hepatic bile acid concentrations may relieve the cholestasis-associated pruritus and slow the progression of hepatocellular degeneration. Although as yet untested, a variation of this therapeutic approach was originally suggested almost 30 years ago by Barbara Billing and colleagues working with Dame Sheila Sherlock , However, the potential hepatoprotective effects of such an intervention must be carefully balanced against any risk of increased bile acid-induced kidney cell injury With the identification of all the major plasma membrane bile acid transporters that maintain the enterohepatic circulation, the focus is shifting toward how these carriers control the extracellular and intracellular levels of bile acids under different physiological and pathophysiological conditions.
In addition to its role as a detergent to solubilize biliary and dietary lipids, bile acids activate a variety of nuclear receptors and signaling pathways 5 , 6. There is a growing appreciation of the role of bile acids as "hormones" to modulate lipid and glucose metabolism 7. By controlling the flux of bile acids in the enterohepatic circulation, the bile acid transporters have an opportunity to modulate bile acid signaling and metabolic regulation.
As such, it will be important to further understand the regulation of these carriers and their relationship to metabolism and human disease. Investigators have also begun to explore the effects of genetic single-nucleotide polymorphisms and epigenetic alterations on transporter expression but much work still needs to be done.
In addition to the bile acid binding resins and ursodeoxycholic acid, new compounds are in development that target bile acid signaling pathways, such as nor-ursodeoxycholic acid, synthetic FXR agonists, FXR modulators, and agonists for the bile acid-activated G-protein coupled receptors 5 , It will be important to understand how these compounds affect the bile acid transporters in animal models and patients.
So, although we have learned a great deal about the bile acid transporters, important questions remain about the role of these important ferrymen in human health and disease. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Bile acid transporters Paul A. Previous Section Next Section. Regulation of BSEP expression and activity BSEP mRNA expression is induced when hepatocyte bile acid levels are elevated, such as following dietary challenge with bile acids , or under certain cholestatic conditions 32 , , Regulation of ASBT expression and activity ASBT is expressed in tissues that serve to facilitate the enterohepatic circulation of bile acids, including the apical membrane of ileal enterocytes, proximal renal convoluted tubule cells, epithelial cells lining the biliary tract cholangiocytes , and gallbladder epithelial cells — Previous Section.
Hofmann A. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Life Sci. CrossRef Medline Google Scholar. Alrefai W. Bile acid transporters: structure, function, regulation and pathophysiological implications. Trauner M. Bile salt transporters: molecular characterization, function, and regulation. Chiang J. Bile acids: regulation of synthesis. J Lipid Res. Thomas C. Targeting bile-acid signalling for metabolic diseases.
Drug Discov. Hylemon P. Bile acids as regulatory molecules.
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Schiff E. Characterization of the kinetics of the passive and active transport mechanisms for bile acid absorption in the small intestine and colon of the rat. Hulzebos C. Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans. Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man.
Cholic acid in healthy man. Medline Google Scholar. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. Control of cholesterol turnover in the mouse. Biological and medical aspects of active ileal transport of bile acids. Kullak-Ublick G. Enterohepatic bile salt transporters in normal physiology and liver disease.
Weinman S. Free concentrations of intracellular fluorescent anions determined by cytoplasmic dialysis of isolated hepatocytes. Lidofsky S. Hepatic taurocholate uptake is electrogenic and influenced by transmembrane potential difference. Reichen J. Uptake of bile acids by perfused rat liver. Van Dyke R. Bile acid transport in cultured rat hepatocytes.
Kouzuki H. Contribution of sodium taurocholate co-transporting polypeptide to the uptake of its possible substrates into rat hepatocytes. Stieger B. ATP-dependent bile-salt transport in canalicular rat liver plasma-membrane vesicles. The bile salt export pump. Pflugers Arch. Akita H. Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Nies A. Lam P. Zollner G. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations.
Soroka C. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hirohashi T. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 Mrp3.
Assem M. Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. Schaap F. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Boyer J. Liver Physiol. Rius M. Marschall H. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver.
Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. Teng S. Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease? Mennone A. Hagenbuch B. The sodium bile salt cotransport family SLC Geyer J.
The solute carrier family SLC more than a family of bile acid transporters regarding function and phylogenetic relationships.
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Naunyn Schmiedebergs Arch. Godoy J. Molecular and phylogenetic characterization of a novel putative membrane transporter SLC10A7 , conserved in vertebrates and bacteria. Cell Biol.
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Sinusoidal basolateral bile salt uptake systems of hepatocytes. Liver Dis. Yale J. Hata S. Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake. Kramer W. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. Platte H. Functional characterization of the hepatic sodium-dependent taurocholate transporter stably transfected into an immortalized liver-derived cell line and V79 fibroblasts.
Mita S. Craddock A. Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Meng L. Transport of the sulfated, amidated bile acid, sulfolithocholyltaurine, into rat hepatocytes is mediated by Oatp1 and Oatp2. Meier P. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.
Kim R. Modulation by drugs of human hepatic sodium-dependent bile acid transporter sodium taurocholate cotransporting polypeptide activity. Drug Metab. Leslie E. Phylogenic and ontogenic expression of hepatocellular bile acid transport. Effect of antisense oligonucleotides on the expression of hepatocellular bile acid and organic anion uptake systems in Xenopus laevis oocytes. Von Dippe P. Carlton V. Hadj-Rabia S. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease.
Geier A. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Anwer M. Cellular regulation of hepatic bile acid transport in health and cholestasis. Karpen S. Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter. Denson L. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp.
Jung D. Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. Rausa F. Elevated levels of hepatocyte nuclear factor 3beta in mouse hepatocytes influence expression of genes involved in bile acid and glucose homeostasis.
Lee Y. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Eloranta J. Hayhurst G. Hepatocyte nuclear factor 4alpha nuclear receptor 2A1 is essential for maintenance of hepatic gene expression and lipid homeostasis. Hepatocyte nuclear factor-4alpha is a central transactivator of the mouse Ntcp gene. Dietrich C. Wang L. Resistance of SHP-null mice to bile acid-induced liver damage. Bochkis I. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress.
Gupta S. Down-regulation of cholesterol 7alpha-hydroxylase CYP7A1 gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. Green R. Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Siewert E. Interleukin-6 regulates hepatic transporters during acute-phase response. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. Vee M. Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-alpha or interleukin Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis.
Lickteig A. Differential regulation of hepatic transporters in the absence of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and nuclear factor-kappaB in two models of cholestasis. Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver.
The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Zimmerman T. Ghose R. Endotoxin leads to rapid subcellular re-localization of hepatic RXRalpha: a novel mechanism for reduced hepatic gene expression in inflammation. Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver. Wang B. Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4 alpha in rat liver. Ktistaki E. Modulation of hepatic gene expression by hepatocyte nuclear factor 1.
Odom D. Control of pancreas and liver gene expression by HNF transcription factors. Cytokine-independent repression of rodent Ntcp in obstructive cholestasis. Gerloff T. Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver. Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride.
Ganguly T. Regulation of the rat liver sodium-dependent bile acid cotransporter gene by prolactin. Mediation of transcriptional activation by Stat5. Cao J. Simon F. Multihormonal regulation of hepatic sinusoidal Ntcp gene expression. Mukhopadhayay S. Grune S. Mukhopadhyay S. Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate.
Dranoff J. Short-term regulation of bile acid uptake by microfilament-dependent translocation of rat ntcp to the plasma membrane. Dephosphorylation of Ser facilitates plasma membrane retention of Ntcp. Webster C. McConkey M. Cross-talk between protein kinases Czeta and B in cyclic AMP-mediated sodium taurocholate co-transporting polypeptide translocation in hepatocytes. Sarkar S. PKCzeta is required for microtubule-based motility of vesicles containing the ntcp transporter. Schonhoff C. Protein kinase Cdelta mediates cyclic adenosine monophosphate-stimulated translocation of sodium taurocholate cotransporting polypeptide and multidrug resistant associated protein 2 in rat hepatocytes.
Noe J. Functional expression of the canalicular bile salt export pump of human liver. Byrne J. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Tomer G. Differential developmental regulation of rat liver canalicular membrane transporters Bsep and Mrp2. Gao B. Differential expression of bile salt and organic anion transporters in developing rat liver.
Strautnieks S. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in families. Hayashi H. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate: a comparison of human BSEP with rat Bsep. Hirano M.
Horikawa M. Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Knisely A.
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Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.
Pauli-Magnus C. Hepatobiliary transporters and drug-induced cholestasis. Dixon P. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Wolters H. Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. Wagner M. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Ananthanarayanan M. Plass J. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump.
Sinal C. Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine. Parks D. Bile acids: natural ligands for an orphan nuclear receptor. Lew J. The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Rizzo G. Kassam A. Hoeke M. Low retinol levels differentially modulate bile salt-induced expression of human and mouse hepatic bile salt transporters.
Oude Elferink R. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Paulusma C. Activity of the bile salt export pump ABCB11 is critically dependent on canalicular membrane cholesterol content.
Folmer D. P4 ATPases - lipid flippases and their role in disease. Biochim Biophys Acta. Cai S. Sure, they look and act the same—but are they numerically identical? Is a transporter really a transporter? One might think that the answer to this question depends on whether Spock2 has the same soul as Spock1. But there are two problems with this answer. A Most philosophers reject the idea that souls exist; our mental activity is not housed in a separable non-material substance but is instead produced by and dependent upon brain activity.
And B having the same soul is not necessary for preserving personal identity. John Locke would have suggested that Star Trek transporters preserve identity because they preserve memory: Spock2 remembers being Spock1. This generates a new theory. Maybe being made of the same atoms is what preserves identity. This like Spock seems logical. But it also causes two problems. First, by this criterion, you are not even the same person as your eight-year-old self. As we grow and live, we shed the cells that make up our bodies and use the matter we ingest to create new ones.
Over a roughly seven-year period, all the matter in your body is replaced. So, you do not now have the same body as your eight-year-old self. Second, this theory would seem to make an afterlife impossible. God, of course, could create someone who looks and acts like you in heaven, out of new material as John Hick suggested , but that would only be a copy of you.
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