scholarly journals Active Enterohepatic Cycling is Not Required for the Choleretic Actions of 24-norUrsodeoxycholic Acid in Mice

2021 ◽  
Author(s):  
Jianing Li ◽  
Jennifer K. Truong ◽  
Kimberly Pachura ◽  
Anuradha Rao ◽  
Sanjeev Gambeer ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Bile Flow ◽  
Organic Anion ◽  
Cholestatic Liver Disease ◽  
Hepatic Expression ◽  
Bile Acid Sequestrants ◽  
Bile Acid Transporters ◽  
Liver Transcriptome ◽  
Bile Acid Transporter

AbstractThe superior ability of norursodeoxycholic acid (norUDCA) to induce a bicarbonate-rich hypercholeresis has been attributed to its ability to undergo cholehepatic shunting and norUDCA is currently being evaluated as a therapeutic for forms of liver disease. The goal of this study was to use mouse models to investigate contributions of bile acid transporters to the choleretic actions of norUDCA. Here, we show that the apical sodium-dependent bile acid transporter (ASBT) and Organic solute transporter-alpha (OSTα) are dispensable for norUDCA-stimulation of bile flow and biliary bicarbonate secretion in mice. Analysis of the liver transcriptome revealed that norUDCA induced hepatic expression of a limited number of transporter genes, particularly organic anion transporting polypeptide 1a4 (Oatp1a4). However, norUDCA potently stimulated a bicarbonate-rich hypercholeresis in Oatp1a/1b-deficient mice. Blocking intestinal bile acid reabsorption by co-administration of an ASBT inhibitor or bile acid sequestrant did not impact the ability of norUDCA to induce bile flow in wildtype mice. The results support the concept that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.

Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid

1996 ◽  
Vol 248 (2) ◽  
pp. 175-185 ◽  
Author(s):  
Mario Fracchia ◽  
Kenneth D.R. Setchell ◽  
Andrea Crosignani ◽  
Mauro Podda ◽  
Nancy O'Connell ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Early Stage ◽  
Cholestatic Liver Disease

Nifedipine modulation of biliary GSH and GSSG/ conjugate efflux in normal and regenerating rat liver

2001 ◽  
Vol 281 (1) ◽  
pp. G85-G94 ◽  
Author(s):  
Bo Yang ◽  
Ceredwyn E. Hill
Keyword(s):  
Bile Acid ◽  
Sodium Nitroprusside ◽  
Rat Liver ◽  
Driving Force ◽  
Bile Flow ◽  
Organic Anion ◽  
High Capacity ◽  
Perfused Rat Liver ◽  
High Affinity ◽  
Glutathione Conjugate Transport

Canalicular glutathione secretion provides the major driving force for bile acid-independent bile flow (BAIF), although the pathways involved are not established. The hypothesis that GSH efflux proceeds by a route functionally distinct from the high-affinity, low-capacity, mrp2-mediated pathway was tested by using perfused rat liver and three choleretic compounds that modify biliary secretion of GSH (the dihydropyridine nifedipine and organic anion probenecid) or GSSG [sodium nitroprusside (SNP)]. Whereas nifedipine (30 μM) stimulated GSH secretion and blocked SNP-stimulated GSSG efflux and choleresis, SNP (1 mM) was ineffective against nifedipine-stimulated GSH efflux or BAIF, suggesting that most GSSG exits through a GSH-inhibitable path independent of high-affinity GSSG/glutathione conjugate transport. Three observations support this proposal. SNP, but not nifedipine, significantly inhibited bromosulfophthalein (BSP, 1 μM) excretion. Probenecid (1 mM) blocked resting or nifedipine-stimulated GSH secretion but only weakly inhibited BSP excretion. Glutathione, but not BSP, efflux capacity was reduced following partial hepatectomy. We suggest GSH efflux is mediated by a high-capacity organic anion pathway capable of GSSG transport when its high-affinity route is saturated.

scholarly journals Growth Hormone Modulation of the Rat Hepatic Bile Transporter System in Endotoxin-Induced Cholestasis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 4008-4017 ◽  
Author(s):  
Dieter Mesotten ◽  
Greet Van den Berghe ◽  
Christopher Liddle ◽  
Sally Coulter ◽  
Fiona McDougall ◽  
...  
Keyword(s):  
Bile Acid ◽  
Organic Anion ◽  
Multiple Organ ◽  
Northern Analysis ◽  
High Dose ◽  
Hepatic Bile ◽  
Gh Treatment ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Transporter Expression

Abstract Treatment with high dose human GH, although an effective anabolic agent, has been associated with increased incidence of sepsis, inflammation, multiple organ failure, and death in critically ill patients. We hypothesized that GH might increase mortality by exacerbating cholestasis through modulation of bile acid transporter expression. High dose GH was continuously infused over 4 d into rats, and on the final day lipopolysaccharides were injected. Hepatic bile acid transporter expression was measured by Northern analysis and immunoblotting and compared with serum markers of cholestasis and endotoxinemia. Compared with non-GH-treated controls, GH increased endotoxin-induced markers of cholestasis and liver damage as well as augmented IL-6 induction. In endotoxinemia, GH treatment significantly induced multidrug resistance-associated protein 1 mRNA and protein and suppressed organic anion transporting polypeptides, Oatp1 and Oatp4, mRNA, suggesting impaired uptake of bilirubin and bile acids at the basolateral surface of the hepatocyte, which could contribute to the observed worsening of cholestasis by GH. This study of endotoxinemia may thus provide a mechanistic link between GH treatment and exacerbation of cholestasis through modulation of basolateral bile acid transporter expression in the rat hepatocyte.

Homo- and heterodimerization is a common feature of the solute carrier family SLC10 members

2019 ◽  
Vol 400 (10) ◽  
pp. 1371-1384 ◽  
Author(s):  
Saskia Noppes ◽  
Simon Franz Müller ◽  
Josefine Bennien ◽  
Matthias Holtemeyer ◽  
Massimo Palatini ◽  
...  
Keyword(s):  
Bile Acid ◽  
Transport Function ◽  
Solute Carrier Family ◽  
Bile Acid Transporters ◽  
Bile Acid Transporter ◽  
Solute Carrier ◽  
Steroid Sulfate ◽  
Functional Relevance ◽  
Two Hybrid

AbstractThe solute carrier family SLC10 consists of seven members, including the bile acid transporters Na+/taurocholate co-transporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter (ASBT), the steroid sulfate transporter SOAT as well as four orphan carriers (SLC10A3, SLC10A4, SLC10A5 and SLC10A7). Previously, homodimerization of NTCP, ASBT and SOAT was described and there is increasing evidence that carrier oligomerization is an important regulatory factor for protein sorting and transport function. In the present study, homo- and heterodimerization were systematically analyzed among all SLC10 carriers (except for SLC10A3) using the yeast-two-hybrid membrane protein system. Strong homodimerization occurred for NTCP/NTCP, ASBT/ASBT and SLC10A7/SLC10A7. Heterodimerization was observed for most of the SLC10 carrier combinations. Heterodimerization of NTCP was additionally investigated by co-localization of NTCP-GFP and NTCP-mScarlet with respective SLC10 carrier constructs. NTCP co-localized with SLC10A4, SLC10A5, SOAT and SLC10A7. This co-localization was most pronounced for SLC10A4 and was additionally confirmed by co-immunoprecipitation. Interestingly, SLC10 carrier co-expression decreased the taurocholate transport function of NTCP for most of the analyzed constructs, indicating that SLC10 carrier heterodimerization is of functional relevance. In conclusion, homo- and heterodimerization is a common feature of the SLC10 carriers. The relevance of this finding for regulation and transport function of the SLC10 carriersin vivoneeds further investigation.

scholarly journals Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0149782 ◽  
Author(s):  
Esther M. Verhaag ◽  
Manon Buist-Homan ◽  
Martijn Koehorst ◽  
Albert K. Groen ◽  
Han Moshage ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Cholestatic Liver Disease

scholarly journals A novel bioluminescence-based method to investigate uptake of bile acids in living cells

2018 ◽  
Vol 315 (4) ◽  
pp. G529-G537 ◽  
Author(s):  
Alexander L. Ticho ◽  
Hyunjin Lee ◽  
Ravinder K. Gill ◽  
Pradeep K. Dudeja ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Real Time ◽  
Sodium Taurocholate ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Bile Acid Transporters ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter

Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01–1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies.NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.

Transport of bile acids in hepatic and non-hepatic tissues

2001 ◽  
Vol 204 (10) ◽  
pp. 1673-1686 ◽  
Author(s):  
M.V. St-Pierre ◽  
G.A. Kullak-Ublick ◽  
B. Hagenbuch ◽  
P.J. Meier
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Organic Anion ◽  
Cholesterol Homeostasis ◽  
Dietary Fats ◽  
Substrate Specificities ◽  
Molecular Defects ◽  
Biliary Epithelium ◽  
Bile Acid Transporters ◽  
Molecular Signals

Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with broad multi-substrate specificities that include bile acids have been discovered. Studies concerning the regulation of these carriers have permitted identification of molecular signals that dictate eventual changes in the uptake or excretion of bile acids, which in turn have profound physiological implications. This overview summarizes and compares all known bile acid transporters and highlights findings that have identified diseases linked to molecular defects in these carriers. Recent advances that have fostered a more complete appreciation for the elaborate disposition of bile acids in humans are emphasized.

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