Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

BACKGROUND: Skeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms. METHODS: We assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber's diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy. RESULTS: UDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber's diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux. CONCLUSIONS: Our results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.

Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice

Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen alpha1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor alpha showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

Oral Solubilized Ursodeoxycholic Acid Therapy in Amyotrophic Lateral Sclerosis: A Randomized Cross-Over Trial

To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial.

Risk Factors for Recurrent Bile Duct Stones after Endoscopic Clearance of Common Bile Duct Stones / 대한소화기학회지

BACKGROUND/AIMS: We aimed to explore the risk factors contributing to the recurrence of common bile duct (CBD) stones after successful endoscopic stone clearance, focused on the anatomical factors of CBD and presence or absence of ursodeoxycholic acid (UDCA)/Rowachol(R) medication. METHODS: One hundred fourteen patients who underwent CBD stone(s) extraction by endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy at our institution from August 2004 to January 2007 were included. Univariate and multivariate analyses for the risk factors including the distal CBD angle, length of the distal CBD arm and medication such as ursodeoxycholic acid (UDCA) and/or Rowachol(R) for recurrent CBD stone(s) were performed. RESULTS: The recurrence of CBD stone(s) was found in 22 (19.3%) patients. On univariate analysis, presence of pneumobilia, presence of type 1 or type 2 periampullary diverticulum, mechanical lithotripsy and multiple sessions of ERCP were significant contributors for the recurrence of CBD stone(s). On multivariate analysis, the presence of type 1 periampullary diverticulum (OR 7.90, 95% CI: 1.56-40.16) and multiple sessions of ERCP (OR 7.56, 95% CI: 2.21-25.87) were significant contributors. Acute distal CBD angulation (< or =135degrees), shorter distal CBD arm (< or =36 mm), technical difficulty of CBD stone(s) clearance, and the prescription of UDCA and/or Rowachol(R) were not significantly associated with the recurrence of CBD stone(s). CONCLUSIONS: The recurrence of CBD stone(s) was more commonly found in the patients group with type 1 periampullary diverticulum and multiple sessions of ERCP. Therefore, patients with these risk factors should be on regular follow up.

Pretreatment with Ursodeoxycholic Acid (UDCA) as a Novel Pharmacological Intervention in Hepatobiliary Scintigraphy

The purpose of this volunteer study was to investigate whether pretreatment with UDCA before the administration of 99mTc DISIDA affects the biliary excretion of the DISIDA, and whether it can shorten the total imaging time. Ten young, healthy volunteers (eight males, two females, mean age: 26.3 +/- 2.1 years) participated in the study. Hepatobiliary scintigraphies were performed twice per volunteer within three days, for the control and the UDCA-pretreated studies. In the control study, the gallbladder (GB) was observed first in four cases and the intestine was observed first in another four cases; in contrast, in the UDCA challenge study, the GB was observed first in eight cases. The quantitative results for the factors related to the GB differed significantly between the control and challenge studies. When the subjects were pretreated with UDCA, the time duration until visualization of the GB was shortened, and the maximum activity of the GB became more intense. In conclusion, UDCA pretreatment before hepatobiliary scintigraphy can shorten the total imaging time for evaluating functional obstructions of the cystic duct and increase the specificity of the process.

Effect of ursodeoxycholic acid on hydrogen peroxide induced lipid peroxidation in sheep liver mitochondria.

The effect of various concentrations of ursodeoxycholic acid (UDCA), a potent hepatoprotective agent on hydrogen peroxide-induced mitochondrial swelling was evaluated in vitro to find out the mechanism of action of the drug. Aliquots of sheep liver mitochondria were pre-incubated with various concentrations of UDCA [0-600 micrograms] and swelling was induced by hydrogen peroxide [1 mM]. Swelling was assessed at various time intervals and lipid peroxide, reduced glutathione status were also evaluated simultaneously. UDCA minimized hydrogen peroxide-induced swelling in a dose-dependent manner. Time-dependent elevation in the level of lipid peroxides was noted in mitochondria treated with hydrogen peroxide and this elevation was minimized in UDCA pre-treatment. UDCA also maintains the reduced glutathione level in mitochondria. UDCA acts against the oxidative stress imposed in liver mitochondria. It reduces lipid peroxidation-induced abnormalities such as swelling and thiol group depletion and the anti lipid peroxidative efficacy of the drug may be related to its hydrophilic nature which might protect the hydrophobic regions of the mitochondrial membranes which are prone for free radical-mediated reactions.

Mecanismos de acción y aplicaciones terapéuticas del ácido ursodeoxicólico en las enfermedades hepáticas colestásicas / Potential mechanisms of action and therapeutic applications of the ursodeoxycholic acid in cholestasis

El ácido ursodeoxicólico es un ácido biliar hidrofílico, que representa una pequeña fracción del pool de ácidos biliares. En las dos últimas décadas, numerosas enfermedades hepáticas colestásicas crónicas (cirrosis biliar primaria, colangitis esclerosante primaria, colestasia intrahepática del embarazo) han sido tratadas con AUDC. Sin embargo, hasta hoy su eficacia sólo ha sido demostrada en la cirrosis biliar primaria, siendo necesario realizar estudios que permitan definir claramente sus indicaciones. Su efecto es mediado por una disminución del daño de los ácidos biliares tóxicos retenidos sobre la membrana celular de los hepatocitos, a través de una estimulación de la secreción biliar, mejoría del flujo biliar y disminución del daño hepático mediado por el sistema inmune

Liver disease in cystic fibrosis

En las últimas dos décadas, la sobrevida de los pacientes con fibrosis quística ha mejorado notablemente, permitiendo la aparición de complicaciones entre las cuales destaca el compromiso hepático. Hasta ahora ha sido difícil detectar la hepatopatía de la fibrosis quística y reconocer sus características. En años recientes se han conseguido progresos en la comprensión de su patogenia, así como una mayor experiencia con ciertas modalidades terapéuticas, lo que se discute en esta revisión

Ursodeoxycholic acid does not interfere with in vivo Helicobacter pylori colonization

A low frequency of Helicobacter pylori in the gastric mucosa of patients with alkaline gastritis has been reported. At the same time, it can be noted that the growth of bacteria can be inhibited by bile acids. We studied 40 patients with chronic gastritis related to Helicobacter pylori in order to determine the effect of ursodeoxycholic acid on this infection. Diagnoses of the infection and the inflammatory process were obtained by histologic study of gastric biopsies collected during endoscopy. Two groups were studied: group I received ursodeoxycholic acid - 300 mg/day, and group II received the placebo, twice a day, both for 28 days. The colonization by Helicobacter pylori and the intensity of the mononuclear and polymorphonuclear inflammatory infiltrate were determined before (time 1) and after (time 2) treatment. Ursodeoxycholic acid had no effect on the Helicobacter pylori infection. A significant reduction in the intensity of the mononuclear inflammatory infiltrate of the gastric antrum mucosa was observed in patients from group I, when we compared not only times 1 and 2 but also groups I and II. However, this was not the case with the body mucosa. We concluded that ursodeoxycholic acid had no action on the colonization by Helicobacter pylori or on the polymorphonuclear inflammatory infiltrate, but it caused a significant reduction in the intensity of the mononuclear inflammatory infiltrate of the gastric antrum