Another mechanism of the cholesterol-lowering effect of bezafibrate may be due to the stimulation of cholesterol efflux from hepatocytes to the bile canaliculi AG-014699 mouse by way of the activation of PPARs. Our experiment using HepaRG cells showed significantly up-regulated expression of ABCG5 and ABCG8 mRNA after bezafibrate but not rifampicin treatment (Fig. 5B). A similar effect of bezafibrate on ABCG5 in human liver has been reported previously.51 Because of the inhibition of bile acid synthesis and presumably the stimulation of cholesterol excretion into bile, bezafibrate significantly increases biliary cholesterol saturation.52 Indeed, increased risk of gallstone formation has been reported in

hyperlipidemic patients treated with another fibrate, fenofibrate.53 However, combination therapy of UDCA and bezafibrate appears to attenuate

the adverse effect of bezafibrate, because UDCA markedly lowers biliary cholesterol saturation and dissolves cholesterol gallstones.2 On the other hand, bezafibrate may augment the anticholestatic and antilithogenic actions of UDCA by inhibiting bile acid synthesis and increasing the proportion of UDCA (Fig. 2C). In addition to anticholestatic effects, activation of PXR54 and the PPARs55 has been reported to suppress inflammation through the inhibition of proinflammatory genes, including nuclear factor-κB (NF-κB), tumor necrosis factor-α, and interleukin-1α. In this study, although we did not evaluate the contribution of the antiinflammatory effects of bezafibrate to the Staurosporine datasheet improvement of biochemical markers, bezafibrate is suggested to be an ideal drug with anticholestatic, hypolipidemic,

and even antiinflammatory actions on PBC by way of the activation of both PXR and PPARs. In summary, bezafibrate exhibited anticholestatic efficacy on PBC patients who showed an incomplete response to UDCA monotherapy. Although UDCA replaces hydrophobic bile acids and activates canalicular BSEP and MDR3 and basolateral MRP4,7 not bezafibrate inhibits hepatic synthesis and uptake of bile acids, enhances bile acid detoxification, and stimulates canalicular MDR3, MDR1 and MRP2 activities as a dual PPARs/PXR agonist (Fig. 6). These data lend support to the idea that combination therapy with UDCA and bezafibrate is an excellent method for the treatment of early-stage PBC patients who exhibit an incomplete biochemical response to UDCA monotherapy. Additional Supporting Information may be found in the online version of this article. “
“The aim of this systematic review was to evaluate the efficacy and safety of biological agents (vedolizumab, abatacept, visilizumab, golimumab) in patients with active moderate to severe ulcerative colitis. This paper was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.

Methods: CHC patients from 1997 to 2012 were included and randomised into a training and validation set (2:1 ratio). Clinical outcomes were determined using population based

data-linkage system. Hyaluronic acid (HA), bilirubin, GGT, α2-macroglobulin, ALT, AST, platelet count, prothrombin time, INR, ALP, creatinine and albumin results were available at entry into the study. The models were developed using cox regression analysis. Results: 617 patients were included: 411 in the training set and 206 in the validation set. Mean follow up was 6yr (range 0.1-14) during which 22 LRD, 23 HCC and 27 LD were observed. Using the training set albumin, GGT, HA, age and sex were chosen in the final model HSP inhibitor to predict 10, 5 and 3yr LRD with AUROC of 0.95 selleck inhibitor (95% CI, 0.91-0.99), 0.95 (95%CI, 0.9-1) and 0.96 (95% CI, 0.91-1) respectively. A cut point of 32.5 had a sensitivity of 80% and specificity of 97% to predict 3yr LRD. A cut point of 31 had a sensitivity of 93% and specificity

of 85% to predict 10yr LRD. Using these two cut points, patients were categorised into 3 risk groups with an annual incidence rate for LRD of 0.1% (95%CI, 0.04-0.2%), 2% (95%CI, 0.3-3.8%) and 13.2% (95%CI, 4.1-22.3%) respectively (p<0.001). Albumin, GGT, HA, age and sex were used to predict 10, 5 and 3yr LD with AUROC of 0.89 (95%CI, 0.8-0.98), 0.9 (95%CI, 0.8-1) and 0.96 (95%CI, 0.93-0.99) respectively. A cut point of 33.5 achieved a sensitivity of 94% and a specificity of 84% to predict 5yr

LD. Using this cut point patients were divided into two risk groups with an annual incidence rate for LD of 0.2% (95%CI, 0.02-0.3%) and 5.8% (95%CI, 2.5-9.1%) respectively (p<0.001). ALP, α2-macroglobulin, age and sex were chosen to predict 10, 5 Phosphoglycerate kinase and 3yr HCC occurrence with AUROC of 0.93 (95%CI, 0.89-0.98), 0.95 (95%CI, 0.91-0.99) and 0.94 (95%CI, 0.90-0.99) respectively. A cut point of 12 had a sensitivity of 90% and specificity of 88% to predict 5yr HCC occurrence. Using this cut point patients were divided into two risk groups with an annual incidence rate for HCC of 0.2% (95%CI, 0.02-0.3%) and 5.6% (95%CI, 3-8.2%) respectively (p<0.001). Similar results were obtained using the validation set. Conclusion: All three simple models had excellent predictive accuracy and were able to stratify risk into clinical meaningful categories. Disclosures: Enrico Rossi – Patent Held/Filed, UNIVERSITY OF WA Gary P. Jeffrey – Advisory Committees or Review Panels: MSD, Novartis The following people have nothing to disclose: Yi Huang, Leon Adams, Gerry C. MacQuillan, Max K. Bulsara Background and Aims: Although HCV-RNA levels are predictive of spontaneous and treatment-induced HCV clearance, factors associated with HCV-RNA levels during early infection remain poorly understood.

A median plasma volume of 5560 mL (range: 3700–9500 mL) was treated. The mean amount of FVIII that was substituted during the MBMP to

achieve CR in patients was 0.196 × 106 IU ± 0.5 × 106 IU. Patients with PR received an average of 0.39 × 106 IU ± 0.26 × 106 IU FVIII concentrate. A median amount of rFVIIa of about 0.66 × 103 (range: 0–8.24 × 103 kIU) was administered. The time course of the development of the FVIII activity and the administered dosages of FVIII for a representative patient are shown in Fig. 1. MBMP  Out of 67 patients, 60 patients underwent MBMP. In 58 patients MBMP was PF-01367338 in vitro completed. Due to catheter occlusion treatment was interrupted in two patients in the third and twelfth treatment cycles, respectively (Fig. 2). Fifty-four patients who completed MBMP achieved CR. PR was achieved in four patients. In this subgroup, malignant disorders with a poor prognosis were diagnosed during the course of the treatment. The improvement of blood clotting owing to our protocol permitted patients to undergo diagnostic steps for tumour staging, including pleurodesis, bone Y-27632 research buy marrow aspiration, lymph node biopsy or mediastinoscopy without bleeding events. Once apheresis started, bleeding was controlled in all 58 patients. Figure 3 indicates the time points at which undetectable inhibitor levels were achieved (Fig. 3a), coagulation factor

concentrates could be discontinued (Fig. 3b) and extracorporeal treatment was discontinued (Fig. 3c). The mean number of apheresis days required to reach these endpoints

was 4.4 days (95% CI 2.9–5.8 days), 17 days (95% CI 14.1–20 d) and 19 days (95% CI 16.2–22.3 days), respectively. The FVIII inhibitor titre correlated with the treatment 17-DMAG (Alvespimycin) HCl days (rs = 0.514, P < 0.01). Conventional treatment  Two patients with moderate clinical bleedings were treated conventionally. The first patient was a young female patient who developed the inhibitor postpartum (FVIII inhibitor titre: 5 BU mL−1, FVIII activity 4%) with mild bleeding symptoms (muscles haematoma). She was treated successfully with steroids over a period of 3 months. The second patient was a 79-year-old man with haemorrhage gastritis and mild muscle haematomas (FVIII inhibitor titre 74 BU mL−1, FVIII activity 4%). He suffered from a severe chronic obstructive lung disease and severe chronic heart failure and was treated successfully with a combination of steroids (1 mg kg−1 BW) and cyclophosphamide (2 mg kg−1 BW) over a period of 9 months. Nevertheless, he experienced a progressive renal failure during immunosuppressive treatment resulting in an increase of serum creatinine from 1.7 mg dL−1 before to 2.9 mg dL−1. Treatment had to be interrupted several times owing to respiratory and urinary infections.

In addition to this epidemiological observation, the relation between allergy and FGID symptoms has been further strengthened through histological and serological evidence pointing to a central mast cell role in the pathogenesis of FGID. Food allergens have been the main suspect. However, tests for food sensitization check details and results with food elimination diets have been inconsistent. In a study of patients with FGID, sensitization to inhaled allergens was found to be in

excess of sensitization to food allergens. We aim to further define the relationship between aeroallergens and FGID. Methods: A prospective study using questionnaires, skin prick test and blood investigation. Consecutive subjects attending allergic clinic, ENT

clinic and gastroenterology clinic were were recruited for this study. We collected data on demographics, atopic and gastrointestinal symptoms with emphasis on allergy history and exposures to aeroallergens. Asthma, allergic rhinitis (AR), eczema and FGID were defined based on internationally validated diagnostic criteria (European Community Respiratory Health Survey II, ARIA, GA2LEN network and ROME III, respectively). We conducted skin prick tests (SPT) to 18 common allergens; total and specific serum IgE levels to 120 allergens were measured by Phadia ImmunoCAP http://www.selleckchem.com/products/PD-0332991.html and ImmunoCAP ISAC. Results: There were 63 subjects. 50% were female and the mean age was 36.6 years (95% CI 33.1–40.2). 36 patients had FGID (32 Functional Dyspepsia, 25 Irritable Bowel Syndrome), 47 AR, 32 eczema and 11 asthma. In non-atopy patients, the prevalence of FGID was 33%. In subjects with asthma the prevalence

of FGID was 100%, while those of eczema and AR were 50% and 57%, respectively. Prevalence of FGID was higher in subjects with more than 1 atopic disease. House dust mites (HDM), an aeroallergen, had the highest sensitization rate of 78% among subjects. Sensitizations Acyl CoA dehydrogenase to HDM and food allergens were not found to be associated with FGID. We found that sensitization to cat dander was significantly higher in IBS vs. non-IBS subjects (72.7% vs. 27.3%, p = 0.017). Pet ownership after the age of 18 years was also associated with IBS (OR 4.19, p = 0.017). However, owning a cat was not a pre-requisite of sensitization to cat dander. Only 2 out of 11 cat sensitizers were previous cat owners. There was a trend of increasing total serum IgE levels in patients with IBS/FD overlap compare with both isolated IBS or FD and no FGID.

5 cells (Fig. 5B). Therefore, in contrast to subgenomic luciferase replicons (Fig. 2; Fig. S4) RNA replication from full-length reporter virus genomes is less efficient in these mouse liver cells compared to the highly permissive Huh-7.5 cell line. Importantly, once ApoE was expressed, all MLT-MAVS−/−miR-122-derived cell lines tested sustained production of infectious reporter virus particles, SCH772984 mw as evidenced by transduction of luciferase activity to naïve Huh-7.5 cells (Fig. 5C). Moreover, when MLT-MAVS−/−miR-122-derived cell lines were transfected

with authentic Jc1 RNA, again expression of ApoE was necessary and sufficient for production of infectious progeny (Fig. 5D). Therefore, full-length HCV genomes efficiently replicate in MLT-MAVS−/−miR-122-derived cell lines and produce infectious progeny, provided that mouse or human ApoE is expressed. We were not able to infect MLT-MAVS−/−miR-122/ApoE cells with mouse CD81-adapted HCVcc (Luc-Jc1mCD81;[2]), which may be due to modest endogenous expression of mCD81, mOCLN, and mCLDN1 (Fig. S3 and data not shown). Thus, we stably expressed either complete or minimal sets of human or mouse entry factors (Table S1). Enhanced receptor expression

was confirmed by FACS (Fig. S3A,B) and immunoblotting (Fig. S3C). Next, we challenged these cells with Luc-Jc1 or mouse CD81-tropic Luc-Jc1mCD81.2 Overall, we buy Alvelestat observed variable efficiencies of infection. Cells expressing complete or minimal sets of human entry receptors (hhhhh and hhhmm) were permissive to both Luc-Jc1 and Luc-Jc1mCD81 (Fig. 6A). Moreover, while Luc-Jc1 was unable to enter cells expressing only mouse receptors (hmmmm or mmmmm), we observed a significant increase in luciferase

activity after inoculation Bcl-w of these cells with Luc-Jc1mCD81, suggesting that mouse-tropic HCVcc particles are able to infect MLT-MAVS−/−miR-122-derived cells in the absence of human entry factors (Fig. 6A). In line with previous observations, Luc-Jc1mCD81 virus entered hhhhh and hhhmm cells more efficiently than Luc-Jc1, indicating a more potent usage of SCARB1, OCLN, and CD81.2 Of note, MLT-MAVS−/−miR-122/hhhmm cells were more permissive to Luc-Jc1 than MLT-MAVS−/−miR-122/hhhhh cells, which may be due to differential expression of CD81 or SCARB1. Importantly, addition of boceprevir during infection reduced luciferase activity to background levels, indicating that transduction of luciferase reflects authentic HCV cell entry and de novo HCV RNA replication. To test if the complete replication cycle can be sustained in these cells, we collected supernatants from these HCV-infected mouse liver-derived cells and used them to inoculate naïve Huh-7.5 cells. Production of infectious particles could not be observed after infection with Luc-Jc1, presumably due to low entry efficiency into mouse liver-derived cells (Fig. 6B).

During the period of observation, CTP ≥7, death (including buy EPZ-6438 those unrelated to liver disease), ascites, and HCC were the most common outcomes experienced by patients. Among patients with baseline fibrosis, 109 progressed to cirrhosis at month 24 and a further 69 had cirrhosis at month 48 (annualized rate of progression to cirrhosis 9.9%) (Table 2). The observed 8-year and calculated annualized incidences of each clinical outcome were three- to four-fold more frequent in the cirrhosis stratum than in the fibrosis stratum (Table 2). Once CTP score rose to ≥7, patients with bridging fibrosis at baseline did not differ from those

with cirrhosis at baseline in the rate of subsequent outcomes. Of 137 study patients with CTP score ≥7 as the first clinical outcome, 93 (69%) had a subsequent clinical outcome after a median time of 11 months; liver-related death or liver transplantation was the most frequent event after a CTP score ≥7, followed by clinical decompensation and ascites (Table 2). Demographic features did not influence outcome rates; the annualized incidence of outcomes,

including progression to cirrhosis, did AZD2014 mouse not differ between men and women or between patients younger versus older than 50 years (P > 0.05) (Table 3). There were too few non-whites or Hispanics to perform meaningful analyses of individual outcomes by ethnic group. A total of 138 deaths were observed during the study (i.e., through October 20, 2009), 82 (59%) of which were

liver-related. After the first 1-2 years of observation, we observed a linear increase in all-cause death and liver-related death for the entire HALT-C Trial population (Figure 2A). The cumulative incidence of all deaths and of liver-related deaths or transplantation was higher among patients who had cirrhosis compared with patients who did not (Figure 2B). Following the development of a CTP score ≥7 (Figure 2C) or a decompensation event (Figure 2D), nearly all deaths were liver-related. At baseline, the prevalence of hypoalbuminemia, thrombocytopenia, and hyperbilirubinemia was higher among patients with cirrhosis than those without cirrhosis (Figure 3A,B). The cumulative 8-year incidence of abnormal levels was higher in the cirrhosis stratum than the fibrosis Mannose-binding protein-associated serine protease stratum for all laboratory markers, except elevated creatinine, which was comparable in both strata (Figure 3A,B). During the observation period, reductions in albumin and in platelet count occurred earlier and more frequently than abnormalities in the other laboratory markers measured. Low platelet count was shown previously to be the best predictor of overall outcomes in the randomized phase of the HALT-C Trial (through 3.5 years), irrespective of stage of fibrosis.17 With further observation, we found that the baseline platelet count was associated closely with the annual rate of initial clinical decompensation.

Radial echoendoscopes give up to a 360° ultrasonographic image perpendicular to the axis of the echoendoscope, and many can perform Doppler selleck chemicals imaging and color-flow mapping. In contrast, linear echoendoscopes give up to a 180° image parallel to the axis of the echoendoscope, allowing for the performance of fine-needle aspiration or injection. Catheter-based

ultrasonographic probes are useful for imaging small mucosal or submucosal lesions and are passed through the accessory channel of a standard endoscope. EUS is generally safe and cost-effective, and can aid in detecting or characterizing common bile duct stones, chronic pancreatitis, subepithelial lesions, and early pancreatic neoplasms. In addition, it plays an important role in the staging of esophageal, gastric, pancreatic, biliary, rectal, and pulmonary tumors. Interventional EUS is increasingly being utilized to relieve pain, decompress pancreaticobiliary ductal obstruction, and in assisting or delivering antitumor treatments. “
“BACKGROUND:

Non-alcoholic fatty liver disease (NAFLD) progresses STA-9090 mw to non-alcoholic steatohepatitis (NASH) in twenty percent of NAFLD patients. The exact mechanisms for disease progression are not entirely clear, although accumulating evidence suggest a role for intestinal barrier dysfunction as permissive in enhancing translocation of microbial products that drive hepatic inflammation and disease progression. The AIM of the present study was to delineate the respective contribution of intestinal epithelial permeability to the pathogenesis Tyrosine-protein kinase BLK of diet-induced NASH in a mouse model of compromised intestinal epithelial permeability due to deletion of the tight junction protein, junctional adhesion molecule A (JAM-A-/-). METHODS: Male C57BL/6j (WT) or JAM-A-/- mice were fed ad libitum either normal diet (ND) or a high fat, high cholesterol diet with 2% fructose water (HFCD). Intestinal epithelial permeability was assessed by in vivo FITC-Dextran permeability assay. Liver tissue injury and inflammation were assessed by histological, RT-qPCR, and

flow cytometric analysis. RESULTS: Within 8 wks of HFCD feeding, JAM-A-/- mice developed steatosis, lobular inflammation, hepatocellular ballooning and fibrosis, which correlated with increased intestinal permeability and serum LPS levels. Only modest NASH-related histologic findings were observed in the HFCD-fed WT mice. Liver injury in the HFCD-fed JAM-A-/- mice was associated with a significant increase in serum transaminases and cholesterol. Increased fibrosis in HFCD-fed JAM-A-/- mice correlated with increased β-smooth muscle actin (βSMA) expression as assessed by immunohis-tochemistry. Markers of hepatic inflammation, toll like receptors 4, 5, and 9; and inflammatory cytokines TNF-β, IL-6 and IL-1β transcript levels were also significantly up regulated in the HFCD-fed JAM-A-/- mice.

The etiology of PCI is still unclear although many theories have been proposed. PCI can develop as a primary idiopathic condition, or secondary to different bronchopulmonary and gastrointestinal diseases. Association of PCI with raised intraabdominal pressure has already been reported. PCI is usually benign condition,

but can present with serious complications such as obstruction, intussusception and intestinal perforation. Different diagnostic modalities are used in the diagnosis of PCI. Colonoscopy findings of multiple, round submucosal protrusions usually with normal overlying mucosa are not conclusive and include lymphoid hyperplasia, hyperplastic polyposis or colitis cystica profunda in differential diagnosis. Barium enema reveals smooth protrusions but can not exclude multiple polypoid lesions. MDCT evaluation with multiplanar reformations and virtual EX 527 purchase colonoscopy resolves the diagnostic problem, revealing gas filled cysts in colonic wall. Ivacaftor datasheet Moreover, MDCT can exclude or detect complications and other pathological conditions such as polyposis, diverticulosis, and tumors. Contributed by

“
“An 80-year-old man was diagnosed with a recurrence of hepatocellular carcinoma on a contrast-enhanced computed tomography (CT) scan (arrow, Figure 1a). The tumor was approximately 8 mm from the liver edge and did not appear to be adjacent to the gastrointestinal tract. After infusion chemotherapy via the hepatic artery, ultrasound-guided radiofrequency ablation was performed under local anesthesia using a single internally cooled electrode with a 2-cm tip exposure. A CT scan obtained 1 day after radiofrequency

ablation showed appropriate necrosis of the tumor until without any apparent complications (arrow, Figure 1b). However, 14 days after radiofrequency ablation, the patient returned to the Emergency Department with abdominal pain. A repeat CT scan showed free air in the mesentery and thickening of the small bowel wall in the mid-abdomen. An early laparotomy was performed and revealed thermal damage to the ileum with a pinhole-sized perforation (arrow, Figure 2) but the damaged ileum was not adherent to the liver. The damaged segment was resected with an end-to-end anastomosis and the patient had an uneventful recovery. Radiofrequency ablation is an effective treatment for hepatocellular carcinoma with complication rates that range from 2% to 10%. Early complications include bleeding into the peritoneal or pleural cavities, perforation of the gastrointestinal tract and the development of a liver abscess. Late complications can include seeding of tumor along the electrode track and the development of strictures within the biliary system. In relation to intestinal perforation, a large multicenter study recorded 7 cases in 2320 patients, a frequency of 0.3%. Two of these patients died.

T HENNESSY,1 R KUMAR,2 A WIGG,2 S NAZARETH,1 R TUMA,1 W CHENG1 1Departments check details of Gastroenterology & Hepatology, Royal Perth Hospital, WA, 2Flinders Medical Centre, Adelaide, SA Intro: Porphyria Cutanea Tarda (PCT), an Extra-Hepatic Manifestation

of Chronic Hepatitis C (CHC) has 5% prevalence. The etiopathogenic role of Hepatitis C virus in PCT is emphasised by the 50% prevalence of CHC in PCT. Reports display that patients with CHC & PCT had a lower Sustained Viral Response (SVR) than those without PCT with standard therapy1 (4.5% versus 27.3%). Limited data exists on the prevalence and Treatment response of PCT in HCV patients in an Australian population. Aims: (1) to determine the prevalence of PCT in our cohort of treated HCV patients. (2) To review our experience in the Treatment of HCV patients in the presence of PCT in 2 Australian tertiary centres. Age Gender Genotype Fibrosis IFN dose (ug) Ribavirin dose Treatment Duration (wks) Response *Treatment stopped due to Viraemia at

Week 24 Results: The prevalence of PCT in HCV patients from 2001–2012 was 0.004% (4/1115) at RPH. Only 7 patients were identified. All were male with mean age of 48(43–54 years). 5 out of 7 patients had genotype 1 and 2 with genotype 3. Treatment duration ranged from 24–48 weeks for treatment naïve patients. 70% were treated with Pegasys. All patients received Ribavirin dose between 1000–1200 mg per day including those with genotype 3. Overall SVR was 42% (3/7) with only 2/5 PI3K inhibitor in genotype 1 achieving SVR. Both patients who were retreated failed to respond to treatment. All patients had venesection prior to HCV Therapy. During the same period SVR in HCV patients without PCT, SVR for genotype 1 was 55% and 63% for Genotype 3. Conclusions: (1) the prevalence of PCT in chronic hepatitis C was low in our small cohort of patients, all being male 6-phosphogluconolactonase (2) SVR in HCV patients with PCT is lower than those without PCT and is consistent with that reported in the literature.

1Fernández et al. Scand J Gastroenterol. 2003 Mar; 38(3):314–319. P PATERIA,1 H CHING,1 G MACQUILLAN,1,2 G P JEFFREY,1,2 G WATTS2,3 D SPEERS,1 L A ADAMS1,2 1Western Australian Liver Transplantation Service, Sir Charles Gairdner Hospital, Perth, WA, Australia, 2School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia, 3Royal Perth Hospital, Perth, WA, Australia Vascular disease is the third leading cause of death in patients with chronic hepatitis C (CHC) infection. CHC may lead to atherosclerosis by increasing pro-atherogenic inflammatory cytokines and insulin resistance in genotype 1 patients. We wished to determine whether patients with CHC infection are at increased risk of atherosclerotic disease and whether genotype or anti-viral treatment modifies this risk. Methods: We performed a case-control study of CHC patients and age and gender matched healthy controls.

5C). Although, after PH, hepatocytes adapted BA synthesis and transport in both genotypes, we found that bile composition in ions did not significantly adapt

Selleck Compound Library in TGR5 KO mice.[5] Because TGR5 is not significantly detected in hepatocytes,[12] TGR5-dependent biliary adaptation after PH most likely reflects processes occurring in cholangiocytes. Our data keep in line with the proposition that TGR5 would control CFTR-dependent Cl− secretion in cholangiocytes,[15] because TGR5 KO exhibited less Cl− secretion in bile than WT mice after PH or BDL. The underlying mechanisms may involve cAMP-dependent membrane targeting of apical sodium-dependent bile salt transporter and CFTR, as previously proposed,[23] although TGR5-dependent signaling pathway transcriptional control of CFTR mRNA remains possible (Supporting Fig. 7B,C). The post-PH increase in HCO3− biliary output, together with biliary pH regulation, may be part of a TGR5-dependent adaptive mechanism enhancing bile secretion and protecting the overloaded remnant liver from BA toxicity.[30, 31] In line with this idea, we observed a post-PH rise in bile viscosity in TGR5 KO mice that may be related to this deficient adaptive response impairing bile flow (Fig. 6D). In addition to the striking phenotype observed in TGR5 KO mice upon BA overload,

further work will be needed to understand how the lack of TGR5 affects basal liver homeostasis (Supporting Fig. 1). We finally found that TGR5 may contribute to BA elimination in urine, at least through the control of MRP2 and MRP4 gene expression in conditions of BA overload. Although nothing has been reported on yet about the role of TGR5 in the kidney,[7, 18] deficient urinary BA elimination worsens liver injury after BDL.[24, 32] In our study, because hepatic necrosis occurs very early on after PH, the default in urinary BA elimination, significantly observed in the days after PH, may more likely result in a worsening of BA overload, rather than in the initiation of liver injury. Interestingly, cAMP is reported as a crucial regulator for MRP2 targeting at

the bile canaliculus,[33] raising the possibility that TGR5-mediated (and cAMP-mediated) post-translational Bumetanide regulation of MRP2 may occur also in kidney epithelial cells. Further studies are needed to identify mechanisms involved in TGR5-mediated regulation of BA efflux in urine. In conclusion, we found that TGR5 protects the liver against BA overload after PH, thereby preserving its regeneration capacity. After PH, BDL, or upon CA-enriched feeding, intrahepatic stasis of abnormally hydrophobic bile may be one of the primary factors involved in liver injury observed in TGR5 KO mice. Moreover, in the setting of BA overload, excessive inflammation as well as impaired urinary BA efflux observed in the absence of TGR5 may worsen liver injury. The authors thank Patrick Pham, Nathalie Samson, Pascale Leblanc-Veyrac, and Noémie Dherbe for their technical help.