Ursodeoxycholate stabilizes phospholipid-rich membranes and mimics the effect of cholesterol: investigations on large unilamellar vesicles

Güldütuna, S.; Deisinger, Barbara; Weiss, Andreas; Freisleben, Hans-Joachim; Zimmer, Guido; Sípos, Péter; Leuschner, U.

doi:10.1016/s0005-2736(97)00030-8

Cited by 41 publications

(34 citation statements)

References 25 publications

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“…Like cholesterol, the incorporation of UDC in the cell membrane maintains stability of the lipid double layer and prevents damage caused by chemical stress. 10 The tendency of UDC to form micelles makes it superior in regard to its membrane protection compared with even more hydrophilic triketo bile salts that are not able to form micelles because of their lack of polar and apolar regions. 14 Histological examination supported the results of our previous study.…”

Section: Discussionmentioning

confidence: 99%

Hydrophilic bile salts protect bile duct epithelium during cold preservation: A scanning electron microscopy study

Hertl¹,

Kluth²,

Broelsch³

2000

Liver Transpl

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Prolonged graft preservation is associated with postoperative bile duct strictures after liver transplantation. We previously showed that hydrophilic bile salts mitigate bile duct preservation injury in a pig model. Because this injury occurs at the epithelial level, scanning electron microscopy was performed to further characterize this effect in vitro. Swine livers were harvested after the intravenous infusion of 1 of 3 solutions: saline (n ‫؍‬ 7), tauroursodeoxycholate ( Scanning electron microscopy is an excellent tool to study injury to bile duct epithelium. This study supports the hypothesis that hydrophilic bile salts protect bile ducts during preservation. To determine whether treatment with hydrophilic bile salts can prevent postoperative stricture, in vivo transplantation studies are needed. Copyright 2000 by the American Association for the Study of Liver DiseasesP rolonged graft preservation is associated with postoperative bile duct strictures after liver transplantation. 1-7 Our hypothesis is that these strictures may be caused by damage to the bile duct epithelium during preservation. We have previously shown that such hydrophilic bile salts as tauroursodeoxycholate (TUDC) and dehydrocholate mitigate preservation injury to the bile ducts for 20 hours in a pig model, whereas such hydrophobic bile salts as taurodeoxycholate (TDC) accelerate the destructive process. 8 Because this injury occurs at the epithelial level, scanning electron microscopy was performed in vitro to evaluate epithelial changes during the preservation time. The time course of injury was also investigated because in the previous report, we collected samples for histological examination after 20 hours of preservation only. 8 Materials and MethodsFifteen male Landrace pigs weighing between 25 and 34 kg were acclimated for at least 1 week before surgery in our animal facility, where they received standard pig chow and water as they wanted. Animals were food-fasted overnight but were allowed water up to the procedure. The experimental protocol was approved by the Animal Ethics Committee of the University of Hamburg (Germany). Experimental DesignIn the control group, 0.9% saline was infused intravenously at a rate of 1.25 mL/min over 20 minutes into control animals (n ϭ 7). In a second group, TUDC (Calbiochem, San Diego, CA) was administered in the same volume at a rate of 2 mol/kg of body weight/min (n ϭ 4). In a third group, TDC (Calbiochem) was administered at the same rate and in the same volume as TUDC (n ϭ 4). The dose administered, as well as the duration of infusion, was derived from previous studies. 8 Surgical ProcedureSurgery was performed as described previously. 8 Briefly, the abdomen was opened under general anesthesia. The cystic duct was ligated close to the gallbladder, and a cannula was introduced into the distal common bile duct and secured. The 20-minute intravenous infusion of TUDC, TDC, or 0.9% saline was then begun. Three minutes before crossclamping, while the infusion continued, 400 IU/kg of body weight of he...

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Section: Discussionmentioning

confidence: 99%

Hydrophilic bile salts protect bile duct epithelium during cold preservation: A scanning electron microscopy study

Hertl¹,

Kluth²,

Broelsch³

2000

Liver Transpl

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“…122,[125][126][127] Stabilization of membrane structures exposed to bile acids has been shown by the addition of ursodeoxycholate or its conjugates. 128,129 Although the nephrotoxicity of bile acids in many clinical conditions has been difficult to identify, functional renal changes and microscopically determined tubular alterations have been shown in patients with obstructive jaundice. 121 Sitprija et al 130 showed that GFR decreased without a change in renal blood flow (RBF) in patients with elevated bilirubin levels (a marker for elevated bile acid levels) of 27 to 40 mg/dL and normal albumin levels (Ն35 g/L).…”

Section: Other Mechanisms Of Renal Injury In the Setting Of Cirrhosismentioning

confidence: 99%

Pathophysiology of renal disease associated with liver disorders: Implications for liver transplantation. Part I

Davis

Gonwa

Wilkinson

2002

Liver Transplantation

117

131

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“…It is known that UDCA has multiple mechanisms of action including stabilization of plasma membrane against cytotoxic bile salt-induced cytolysis, 18) and prevention of cytotoxic bile saltinduced apoptosis. 19) Furthermore, cholehepatic shunting of UDCA will promote the removal of cytotoxic bile from bile acid pool.…”

Section: Vil2mentioning

confidence: 99%

Ursodeoxycholic Acid Ameliorates Intrahepatic Cholestasis Independent of Biliary Bicarbonate Secretion in Vil2kd/kd Mice

Hatano

Kawaguchi

Togashi

et al. 2017

Biological & Pharmaceutical Bulletin

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Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that possesses many pharmacological effects, including increasing bile flow, changing the hydrophobicity of the bile acid pool, and modulation of the immune response. UDCA has been approved for treating cholestatic liver disease, such as primary biliary cholangitis. However, several unanticipated severe side effects of UDCA are observed in cholestatic patients, and its pharmacological benefits remain controversial. We reported that ezrin-knockdown (Vil2 kd/kd ) mice exhibited severe hepatic injury because of a functional disorder in bile duct fluidity and alkalinity regulation, resembling human intrahepatic cholestatic disease. Here we used Vil2 kd/kd mice as a cholestatic model to investigate the pharmacological effects of UDCA. We investigated the effects of oral and parenteral administration of UDCA on Vil2 kd/kd mice. In Vil2 kd/kd mice, fed a 0.5% (w/w) UDCA diet for 3 weeks, hepatic injury was exacerbated, although oral administration of a lower dose of UDCA slightly improved hepatic function in Vil2 kd/kd mice. On the other hand, intraperitoneal administration of UDCA (50 mg/kg/d) ameliorated hepatic function and markedly reduced periductal fibrosis and cholangiocyte proliferation in Vil2 kd/kd mice although biliary pH and HCO 3 concentration were not improved. The expression levels of inflammatory and profibrotic genes were also significantly decreased in these mice. Furthermore, UDCA prevented cholangiocytes from hydrophobic bile acid-induced cytotoxicity independent of extracellular pH in in vitro experiments. These results suggest that an appropriate dosage of UDCA can ameliorate the intrahepatic cholestasis in Vil2 kd/kd mice without changing the biliary bicarbonate secretion.

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Ursodeoxycholate stabilizes phospholipid-rich membranes and mimics the effect of cholesterol: investigations on large unilamellar vesicles

Cited by 41 publications

References 25 publications

Hydrophilic bile salts protect bile duct epithelium during cold preservation: A scanning electron microscopy study

Hydrophilic bile salts protect bile duct epithelium during cold preservation: A scanning electron microscopy study

Pathophysiology of renal disease associated with liver disorders: Implications for liver transplantation. Part I

Ursodeoxycholic Acid Ameliorates Intrahepatic Cholestasis Independent of Biliary Bicarbonate Secretion in <i>Vil2<sup>kd</sup></i><sup>/</sup><i><sup>kd</sup></i> Mice

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