Effect Of Ursodeoxycholic Acid Research Articles

The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.

The Effects of Ursodeoxycholic Acid Pretreatment in an Experimental Setting of Extended Hepatectomy: A Feasibility Study

IntroductionLiver regeneration is an exceptionally complex process, orchestrated by a multitude of growth factors and cytokines. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (Il-6) have a pivotal role in the initiation of the regenerative response. Ursodeoxycholic acid (UDCA) exhibits a liver protective effect that enhances liver growth after injury. The aim of the present study is to evaluate the effect of UDCA in the circulating levels of TNF-a and Il-6 in rats undergoing extended 80% hepatectomy.Materials and methodsTwenty-two male Sprague Dawley rats were randomly assigned in an experimental (UDCA group) and a control group. Mice in the UDCA-group received oral pretreatment of UDCA for two weeks preoperatively at a dosage of 25 mg/kg/day. An 80% hepatic resection was performed in both groups by resecting the middle, inferior right, and left lateral liver lobes. The experiment ended 48 hours postoperatively.ResultsUDCA pretreatment significantly depressed circulating levels of both TNF-a and Il-6 after the conclusion of the experiment as compared to the control group (p=0.001 and p=0.01, respectively). Furthermore, TNF-a levels were significantly reduced before the institution of liver injury (p=0.02). Mice in the UDCA-group exhibited better liver growth as demonstrated by significantly increased Ki-67 and mitotic rate (p=0.04 and p=0.02, respectively). Finally, the liver regeneration rate (LRR) was significantly elevated in the experimental group (UDCA group, 54.5% vs control group, 35.8%; p=0.002) signifying enhanced liver growth kinetics.ConclusionUDCA reduces the expression of TNF-a and Il-6 during the priming phase of liver regeneration. An 80% hepatectomy model of acute liver failure exhibited enhanced liver regeneration in the experimental group, plausibly due to the immunomodulatory effects of UDCA.

Erratum: Mayevskaya M.V. et al., “An Effect of Ursodeoxycholic Acid on Inflammation, Steatosis and Liver Fibrosis and Atherogenesis Factors in Patients with Non-Alcoholic Fatty Liver Disease: Results of the USPEH Study”

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Effect of ursodeoxycholic acid in facilitating early hepatic clearance of radiotracer among patients undergoing 99mTc-sestamibi myocardial perfusion scintigraphy: A randomized double blind placebo controlled parallel trial

BackgroundInfra-cardiac tracer activity due to persistent hepatic activity interferes in inferior and infero-septal wall assessment during 99mTc-MIBI SPECT/CT myocardial perfusion scintigraphy (MPS) in evaluation of patients with coronary artery disease. It affects image interpretation with increased study duration. Ursodeoxycholic acid (UDCA) is known to enhance hepatic excretion of bilirubin and bile salts, though its role in enhancing the hepatic tracer clearance in facilitating cardiac imaging is not known. MethodsThis prospective, randomized double-blind, placebo controlled clinical trial of 120 patients, referred for adenosine stress or viability MPS studies were randomized 1:1 to receive either UDCA or placebo. Outcome was quantitative & qualitative improvement in imaging for better interpretation and to reduce the waiting time for scan. Results118 participants (59 ± 11.9 years; 84 men) underwent adenosine stress MPS or viability MPS. Sixty participants had UDCA while 58 had placebo intervention. The study showed significant decrease in liver counts with improved myocardial to liver ratio at 30 and 60 minutes in adenosine stress MPS group, and marginally significant alteration in liver counts at 60 minutes in viability MPS group receiving UDCA, resulting in better images. ConclusionUDCA intervention in MPS provides early and better image due to faster hepatic tracer clearance.

Pleiotropic effects of ursodeoxycholic acid in patients with non-alcoholic steatohepatitis with impaired glycemic control

The goal was to determine the effect of ursodeoxycholic acid (UDCA) in non-alcoholic steatohepatitis (NASH) with impaired glycemic control.Materials and methods. 67 patients NASH were examined: prediabetes — 38 (56.7%), type 2 diabetes mellitus 29 (43.3%), men — 39 (58.2%), women — 28 (41.8%), age — 45.1 ± 10.2 years. The UDCA dose was 9.4 ± 2.0 mg / kg / day during 59.7 ± 77.6 weeks. Fragments of cytokeratin-18 (FCK-18) (TPS ELISA, Biotech, Sweden), TNF-α (Human TNFα Platinum ELISA, eBioscience, Austria), IL-6 (“Interleukin-6-IFA-Best”, Vector-Best, Russia), insulin (“Insulin TEST System”, Monobind Inc., USA), HOMA-IR were determined.Results. There was a decrease in the levels of FCK-18 — from 238.1 ± 93.7 to 170.7 ± 79.2 U / l (p <0.05), ALT — 61.3 ± 19.0 to 38.9 ± 19.1 U / l (p <0.05), glucose 5.9 ± 1.3 to 5.5 ± 0.7 mmol / l (p <0.05), insulin 21.9 ± 18.2 to 13.7 ± 9.7 MkU / l, HOMA-IR — 5.8 ± 2.2 to 3.1 ± 0.8 (p <0.05), cholesterol — 6.2 ± 0.9 to 5.3 ± 0.3 mmol / l, LDL — 3.9 ± 0.9 to 3.2 ± 0.6 mmol / l (p <0.05), TNF-α 6.3 ± 1.5 to 5.4 ± 2.1 pg / ml (p <0.05), IL-6–7.1 ± 3.4 to 4, 1 ± 3.2 pg / ml (p <0.05).Conclusion. UDCA had pleiotropic effects in NASH with impaired glycemic control, reducing cellular apoptosis, necrosis, inflammation, improving insulin sensitivity and lipid homeostasis.

What are the effects of ursodeoxycholic acid (UDCA) for treating intrahepatic cholestasis of pregnancy?

What are the effects of ursodeoxycholic acid (UDCA) for treating intrahepatic cholestasis of pregnancy?

The effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy: a randomized clinical trial

Objectives Indirect hyperbilirubinemia during neonatal period is a common problem, and most preterm and more than half of the term neonates find this problem. Ursodeoxycholic acid (UDCA) protects the liver against oxidative stresses and prevents cellular apoptosis. In addition, it causes stimulation of bile flow, is well tolerated by the patient, and has limited side effects. Thus, the aim of this study was to investigate the effect of UDCA in treating neonates with unconjugated hyperbilirubinemia undergoing phototherapy. Methods In this randomized clinical trial, 220 neonates with unconjugated hyperbilirubinemia who referred to Amir-Kabir Hospital, Arak, Iran in 2017–2018, were randomly assigned to phototherapy group (Control group) and phototherapy plus UDCA group (Intervention group) as 10 mg/kg/day. The level of total bilirubin was measured at the baseline, and after 12, and 24 h using spectrophotometric, and the duration of receiving phototherapy was also measured in both groups. Results The mean age of included neonates in the control and intervention group was 5.3 and 4.9 days, respectively. The results revealed that after 12 h of treatment, the total bilirubin level in the control group had diminished by 2.70 mg/dL on average while, in the intervention group, the reduction was 3.7 md/dL (p = .001) and after 24 h of treatment, the total bilirubin level in the control group had diminished by 5.22 mg/dL on average and in the intervention group, the reduction was 6.54 md/dL (p = .001). It was also observed that there is no significant difference between groups in terms of the mean of the duration required for phototherapy (p = .63). Conclusions UDCA combined with phototherapy enhances TSB decrease, but this effect is not relevant from a clinical point of view because it does not decrease phototherapy and hospital stay duration. Thus, this study does not support the UDCA use in the clinical practice Trial registration IRCT, IRCT2017071515511N2. Registered 21 Aug 2017 – Retrospectively registered, https://en.irct.ir/trial/14763.

Ursodeoxycholic acid protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis in MPTP/MPP+-induced Parkinson’s disease

Neuroprotection targeting mitochondrial dysfunction has been proposed as a potential therapeutic strategy for Parkinson’s disease (PD). Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage; however, the role of UDCA in PD is poorly understood. This study aimed to investigate the neuroprotective effects of UDCA on PD and its underlying mechanisms. We used MPTP/MPP+-induced PD models, including MPTP-induced mice, primary cultures of mice mesencephalic neurons and MPP+-treated neuro-2a cells to examine the effects of UDCA on PD pathogenesis. The results showed that UDCA improved behavioral performance and protected dopaminergic neurons in MPTP mice. UDCA improved cell viability and decreased cell death in MPP+-treated cells. UDCA inhibited reactive oxygen species accumulation, mitochondrial membrane potential collapse, and ATP depletion in neuro-2a cells. UDCA improved movement dysfunction, ameliorated autophagic flux and alleviated apoptosis. Furthermore, UDCA could activate the AMPK/mTOR and PINK1/Parkin pathways. In conclusion, UDCA may improve PD by regulating mitochondrial function, autophagy, and apoptosis, involving AMPK/mTOR and PINK1/Parkin pathways. These results open new perspectives for pharmacological use of UDCA in PD.

Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life‐threatening disease with a high mortality rate, which was a common complication of fat embolism syndrome (FES). Ursodeoxycholic acid (UDCA) has been reported to exert potent anti‐inflammatory effects under various conditions. In vivo, perinephric fat was injected via tail vein to establish a rat FES model, the anti‐inflammatory effects of UDCA on FES‐induced lung injury were investigated through histological examination, ELISA, qRT‐PCR, Western blot and immunofluorescence. In vitro, human lung microvascular endothelial cells (HPMECs) were employed to understand the protective effects of UDCA. The extent of ALI/ARDS was evaluated and validated by reduced PaO2/FiO2 ratios, increased lung wet/dry (W/D) ratios and impaired alveolar‐capillary barrier, up‐regulation of ALI‐related proteins in lung tissues (including myeloperoxidase [MPO], vascular cell adhesion molecule 1 [VCAM‐1], intercellular cell adhesion molecule‐1 [ICAM‐1]), elevated protein concentration and increased proinflammatory cytokines levels (TNF‐α and IL‐1β) in bronchoalveolar lavage fluid (BALF). Pre‐treatment with UDCA remarkably alleviated these pathologic and biochemical changes of FES‐induced ALI/ARDS; our data demonstrated that pre‐treatment with UDCA attenuated the pathologic and biochemical changes of FES‐induced ARDS, which provided a possible preventive therapy for lung injury caused by FES.

Changes in plasma bile acids are associated with gallbladder stones and polyps

BackgroundThe development of gallbladder disease (GBD) is related to bile acid (BA) metabolism, and the rate of BA circulation increases the risk of biliary cancer. However, it is unclear whether patterns of circulating bile acids (BAs) change in patients with benign GBDs such as gallbladder stones and polyps. Herein, we compared and characterised plasma BA profiles in patients with cholecystolithiasis and non-neoplastic polyps with healthy controls, and explored relationships between plasma BA profiles, demographics, and laboratory test indices.MethodsA total of 330 subjects (13 healthy controls, 292 cholecystolithiasis and 25 non-neoplastic polyps) were recruited and plasma BA profiles including 14 metabolites from patients with pathologically confirmed cholecystolithiasis and non-neoplastic polyps were compared with controls. BAs were quantitated by liquid chromatography and mass spectrometry, and statistical and regression analyses of demographics and laboratory test indices were performed.ResultsFemales displayed a higher burden of GBD than males (63.36% cholecystolithiasis, 60% non-neoplastic polyps). Cholecystolithiasis and non-neoplastic polyps were associated with increased plasma total secondary BAs, while levels of primary BAs were lower than in healthy controls. Plasma ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycyurdeoxycholic acid (GUDCA), taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) were decreased significantly in GBDs, and ursodeoxycholic acid (UDCA) was negatively correlated with white blood cell count and neutrophil percentage.ConclusionsSecondary BA levels were higher in patients with cholecystolithiasis and non-neoplastic polyps. White blood cell count and percentage of neutrophil in peripheral blood were negatively correlated with UDCA, indicating an anti-inflammation effect of UDCA.

Ursodeoxycholic Acid Protects Against Arsenic Induced Hepatotoxicity by the Nrf2 Signaling Pathway.

Arsenic is ubiquitous toxic metalloid responsible for many human diseases all over the world. Contrastingly, Ursodeoxycholic acid (UDCA) has been suggested as efficient antioxidant in various liver diseases. However, there are no reports of the effects of UDCA on arsenious acid [As(III)]-induced hepatotoxicity. The objective of this study is to elucidate the protective actions of UDCA on As(III)-induced hepatotoxicity and explore its controlling role in biomolecular mechanisms in vivo and in vitro. The remarkable liver damage induced by As(III) was ameliorated by treatment with UDCA, as reflected by reduced histopathological changes of liver and elevation of serum AST, ALT levels. UDCA play a critical role in stabilization of cellular membrane potential, inhibition of apoptosis and LDH leakage in LO2 cells. Meanwhile, the activities of SOD, CAT and GSH-Px and the level of TSH, GSH were enhanced with UDCA administration, while the accumulations of intracellular ROS, MDA and rate of GSSG/GSH were decreased in vivo and in vitro. Further study disclosed that UDCA significantly inhibited As(III)-induced apoptosis through increasing the expression of Bcl-2 and decreasing the expression of Bax, p53, Cyt C, Cleaved caspase-3 and 9. Moreover, UDCA promoted the expression of nuclear Nrf2, HO-1, and NQO1, although arsenic regulated nuclear translocation of Nrf2 positively. When Nrf2 was silenced, the protective effect of UDCA was abolished. Collectively, the results of this study showed that UDCA protects hepatocytes antagonize As(III)-induced cytotoxicity, and its mechanism may be related to activation of Nrf2 signaling.

Ursodeoxycholic acid protects neonatal rats from necrotizing enterocolitis: a biochemical, histopathological, and immunohistochemical study

Background The pathophysiology of necrotizing enterocolitis (NEC) includes the massive production of endogenous cytokines with exaggerated activation of inflammatory pathways. Ursodeoxycholic acid (UDCA) has been used as an anti-inflammatory, antioxidant, and anti-apoptotic agent. We investigated the possible protective effects of UDCA in a neonatal rat pup model of NEC. Methods We randomly divided rat pups into three groups: a control group, a non-treated NEC group, and a UDCA-treated NEC group. We induced NEC by feeding formula enterally and via hypoxia/reoxygenation. Intestinal samples were collected for histopathological and immunohistochemical evaluation. Blood samples were taken for biochemical analyses. Results UDCA significantly reduced the extents of terminal ileal and jejunal injuries compared to the NEC group (p < .01), reduced Bax and caspase-3 immunoreactivities (both p < .01), and lowered serum levels of platelet-activating factor and intestinal fatty acid-binding protein (p < .01, p = .023, respectively). Conclusions In a rat model of NEC, UDCA protects against adverse intestinal histological, immunohistochemical, and biochemical changes. UDCA significantly reduces the effects of NEC on the rat pup intestine.

The combined application of Ursodeoxycholic acid (UDCA) and probiotic complex ProbioLog may affect lithogenesis processes in the early stages of gallstone disease in elderly people

The aim of the study was to evaluate the effectiveness of ursodeoxycholic acid (UDCA) in combination with ProbioLog at the early stage of gallstone disease in the elderly.Material and methods: 92 patients with early stage of cholelithiasis (CL) were examined, the average age was 66,69 ± 5,52 years, there were 29 men and 63 women. In addition to anamnestic and general clinical data, the results of ultrasound examination (US) of the gallbladder were used to verify the diagnosis. The biochemical properties of bile (cholesterol, bile acids, phospholipids levels, bile lithogenicity indices) were studied. The composition of the intestinal microflora was determined using a hydrogen breath test with lactulose and culture of feces for dysbiosis. Two groups were formed due to the course of treatment, which amounted to 30 days. 45 patients of the observation group received UDCA 15 mg / kg per day once for a night in combination with the probiotic ProbioLog (Mayoly Spindler, France), 1 сapsule twice per day. UDCA monotherapy of 15 mg / kg daily was administered to 47 patients of the comparison group once for the night.Results. After the course of treatment, a favorable dynamics of clinical symptoms of the disease was noted. According to US, elimination of biliary sludge was observed in 62.2% of patients of the observation group and in 14.8% of patients of the comparison group. An improvement in the biochemical composition of bile was manifested by decreasing of its lithogenic properties. The important results of therapy were positive changes in the composition of the intestinal microflora, contributing to the normalization of the exchange of bile acids, cholesterol and phospholipids.Conclusion. The combined using of UDCA and ProbioLog in elderly patients is clinically effective in the treatment of early stages of cholelithiasis and pathogenetically justified in the prevention of gallstone formation.

Prolonged ursodeoxycholic acid administration reduces acute ischaemia-induced arrhythmias in adult rat hearts

Acute myocardial ischaemia and reperfusion (I–R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague–Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

Preparation and characterization of sorafenib-loaded microprecipitated bulk powder for enhancing oral bioavailability.

The aim of this study was to prepare and evaluate Eudragit-based microprecipitated bulk powder (MBP) formulations to enhance the oral bioavailability of sorafenib. Cationic Eudragit E PO and anionic Eudragit S100 were selected for MBP preparation. Ursodeoxycholic acid (UDCA)-incorporated MBP was also prepared to study the synergistic effect of UDCA in enhancing the bioavailability of sorafenib. Sorafenib-loaded MBPs were successfully prepared by a pH-controlled precipitation method using an aqueous antisolvent. Submicron-sized particles of MBPs were observed by scanning electron microscopy, and the amorphous form of sorafenib in MBPs was confirmed by powder X-ray diffraction. MBPs of cationic and anionic Eudragits showed different in vitro dissolution and pharmacokinetic profiles in rats. Sorafenib in Eudragit E PO-based MBP (E PO-MBP) was rapidly dissolved at low pH conditions (pH 1.2 and 4.0), but was precipitated again at pH 4.0 within 4h. Dissolution of sorafenib from Eudragit S100-based MBP (S100-MBP) was high at pH 7.4 and did not precipitate for up to 4h. After oral administration to rats, all MBPs, compared with powder, improved the oral absorption of sorafenib, with S100-MBP showing 1.5-fold higher relative oral bioavailability than E PO-MBP. Moreover, incorporation of UDCA in S100-MBP (S100-UDCA-MBP) further increased the Cmax and oral bioavailability of sorafenib, although the dissolution was not significantly different from that of S100-MBP. Taken together, Eudragit-based MBP formulations could be a promising strategy for enhancing the oral bioavailability of sorafenib.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: statistical analysis plan for a randomised controlled trial (UPGRADE trial)

BackgroundApproximately 8–15% of patients undergoing bariatric surgery develop symptomatic gallstone disease within 24 months after surgery. Ursodeoxycholic acid (UDCA) seems to effectively prevent the formation of gallstones detectable by ultrasound after bariatric surgery. The aim of the UPGRADE trial is to provide evidence on the prophylactic use of UDCA in preventing symptomatic gallstone disease postoperatively.MethodsThe UPGRADE trial is designed as a randomised, placebo-controlled, double-blind multicentre trial in patients with morbid obesity undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Patients are randomly assigned to either UDCA 900 mg daily for 6 months or placebo treatment. This paper details the statistical analysis plan (SAP) of this trial and was submitted before outcome data were available.ResultsThe primary endpoint of this trial is symptomatic gallstone disease within 24 months after bariatric surgery, defined as admission or hospital visit for symptomatic gallstone disease. Secondary outcomes consist of the development of gallstones/sludge on ultrasound at 24 months in the gallstone-negative group at baseline, presence of gallstones/sludge on ultrasound at 24 months, number of cholecystectomies, side effects of UDCA, therapy compliance, quality of life, costs and revenues. Analyses will be completed according to this pre-specified SAP. The main analysis will be performed as a standard ITT analysis using the chi-squared test.DiscussionThe UPGRADE trial will show if prophylactic use of UDCA reduces the incidence of symptomatic gallstone disease after bariatric surgery. Unforeseen deviations from the SAP at the time of analysis will be motivated and discussed.Trial registrationThe Netherlands Trial Register NL5954. Registered on 21 November 2016.

Role of mitochondria in the differential action of sodium deoxycholate and ursodeoxycholic acid on rat duodenum.

Sodium deoxycholate (NaDOC) inhibits the intestinal Ca2+ absorption and ursodeoxycholic acid (UDCA) stimulates it. The aim of this study was to determine whether NaDOC and UDCA produce differential effects on the redox state of duodenal mitochondria altering the Krebs cycle and the electron transport chain (ETC) functioning, which could lead to perturbations in the mitochondrial dynamics and biogenesis. Rat intestinal mitochondria were isolated from untreated and treated animals with either NaDOC, UDCA, or both. Krebs cycle enzymes, ETC components, ATP synthase, and mitochondrial dynamics and biogenesis markers were determined. NaDOC decreased isocitrate dehydrogenase (ICDH) and malate dehydrogenase activities affecting the ETC and ATP synthesis. NaDOC also induced oxidative stress and increased the superoxide dismutase activity and impaired the mitochondrial biogenesis and functionality. UDCA increased the activities of ICDH and complex II of ETC. The combination of both bile acids conserved the functional activities of Krebs cycle enzymes, ETC components, oxidative phosphorylation, and mitochondrial biogenesis. In conclusion, the inhibitory effect of NaDOC on intestinal Ca2+ absorption is mediated by mitochondrial dysfunction, which is avoided by UDCA. The stimulatory effect of UDCA alone is associated with amelioration of mitochondrial functioning. This knowledge could improve treatment of diseases that affect the intestinal Ca2+ absorption.

The effect of ursodeoxycholic acid on the relative expression of the lipid metabolism genes in mouse cholesterol gallstone models

BackgroundMany studies indicate that gallstone formation has genetic components. The abnormal expression of lipid-related genes could be the basis for particular forms of cholesterol gallstone disease. The aim of this study was to obtain insight into lipid metabolism disorder during cholesterol gallstone formation and to evaluate the effect of ursodeoxycholic acid (UDCA) on the improvement of bile lithogenicity and its potential influence on the transcription of lipid-related genes.MethodsGallstone-susceptible mouse models were induced by feeding with a lithogenic diet (LD) for 8 weeks. Bile and liver tissues were obtained from these mouse models after 0, 4 and 8 weeks. Bile lipids were measured enzymatically, and the cholesterol saturation index (CSI) was calculated to evaluate the bile lithogenicity by using Carey’s critical tables. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA expression levels of farnesoid X receptor (FXR), liver X receptor (LXR), adenosine triphosphate-binding cassette subfamily G member 5/8 (ABCG5/8), cholesterol 7-α hydroxylase (CYP7A1), oxysterol 7-α hydroxylase (CYP7B1), sterol 27-α hydroxylase (CYP27A1), peroxisome proliferator-activated receptor alpha (PPAR-α) and adenosine triphosphate-binding cassette subfamily B member 11 (ABCB11).ResultsThe rate of gallstone formation was 100% in the 4-week group but only 30% in the UDCA-treated group. The UDCA-treated group had a significantly lower CSI compared with other groups. Of special note, the data on the effects of UDCA showed higher expression levels of ABCG8, ABCB11 and CYP27A1, as well as lower expression levels of LXR and PPAR-α, compared to the model control group.ConclusionsUDCA exhibits tremendously potent activity in restraining lipid accumulation, thus reversing the lithogenic effect and protecting hepatocytes from serious pathological damage. The abnormal expression of ABCG8, CYP7A1, CYP27A1, LXR and PPAR-α might lead to high lithogenicity of bile. These results are helpful in exploring new lipid metabolism pathways and potential targets for the treatment of cholesterol stones and for providing some basis for the study of the pathogenesis and genetic characteristics of cholelithiasis. Research on the mechanism of UDCA in improving lipid metabolism and bile lithogenicity may be helpful for clinical treatment and for reducing the incidence of gallstones.

The effects of ursodeoxycholic acid on sepsis-induced cholestasis management in an animal model

ObjectivesCholestasis refers to a reduction in bile flow from the liver into the biliary system. Ursodeoxycholic acid (UDCA) is commonly used for the treatment of hepatic cholestasis. This study aimed to explore the role of UDCA in the treatment and prevention of lipopolysaccharide (LPS)-induced cholestasis. MethodsSixty male albino rats were randomly classified into five groups of 12 rats each: the control group (received saline and water), UDCA group (received UDCA), LPS group (received LPS), treatment group (received LPS followed by UDCA), and prevention group (received UDCA followed by LPS). Changes in gamma-glutamyl transferase (GGT), plasma aspartate transferase (AST), plasma alkaline transferase (ALT), plasma alkaline phosphatase (ALP), total bilirubin (TBIL), hepatocyte apoptosis, immunomodulatory activity, plasma pro-inflammatory cytokines (TNF-α, IL-1α, and IL-4), and liver histology were assessed. ResultsUDCA improved serum liver chemical markers (GGT, ALP, and AST) in both the prevention and treatment groups (p < 0.05 and p < 0.05, respectively). CD3 count was higher in the UDCA treatment group compared to the LPS group (p < 0.001). UDCA caused a reduction in plasma TNF-α in the prevention group (P < 0.05); however, it had no effect on the treatment group, as compared to the LPS group. Similarly, UDCA had no effect on IL-1α or IL-4. UDCA treatment resulted in improved liver histological features and a significant reduction in liver tissue apoptosis in both the treatment and prevention groups, as compared to the LPS group (p = 0.013 and p = 0.002, respectively). ConclusionsThis study provides evidence of the effectiveness of UDCA for the treatment and prevention of sepsis-induced cholestasis.

Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy

Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.