Thus, 5 to 20% of NAFL patients progress to NASH. It is still not well understood why some patients develop NASH selleck compound and others remain with NAFL. Higher frequencies of Th17 cells were observed in livers of a NASH mouse model and higher IL-17 and IL-21 gene expression was described

in human livers of NASH patients. We hypothesized that the phenotype of peripheral CD4+ T cells might be predictive for the degree and quality of hepatic T cell infiltration and histopathology. Aims: To analyse differences in the hepatic and peripheral immune phenotype in patients with NAFL and NAFLD with a focus on conventional CD4+ effector T cell subsets and CD4+ regulatory T cells (Tregs). Methods: 40 patients with NAFL, 17 patients with NASH and 44 healthy controls (HC) were included in this study. Multi-colour FACS analysis was performed of PBMCs and intrahepatic lymphocytes. CD4+ T cells were stimulated with PMA and ionomycin for intracellular detection of cytokine production (IL-17, IL-4, INF-g, IL-21). Results: Patients were older, had a higher BMI and a higher CK-18 serum level in comparison to HC. In peripheral blood, NAFLD and NASH patients had higher frequencies of HLA-DR+, i.e. activated, effector memory, IFN-g+, IL-17+, IL-21+ and IL-4+ cells and lower frequencies of CD45RA+ CD25+ resting Tregs among CD4+ T cells than HC. Closer analysis of Th1 cells among PBMCs revealed that T-bet expression

was lower among CXCR3+ cells of NASH than NAFLD patients. The CD4+ T cells infiltrating the liver of NAFLD and NASH patients consisted to more than 80% of CXCR3+ effector memory cells with more than 50% SCH 900776 in vivo recently activated, i.e. HLA-DR+, cells and frequencies of cells producing the named cytokines elevated at least five- to ten-fold in comparison to PBMCs. Higher frequencies of IL-17+ cells among intrahepatic CD4+ T cells and a higher Th17/ resting Treg ratio distinguished NAFLD from NASH patients. Conclusions: Our data indicate that NAFL patients show a “prehepatitic” immune cell profile very similar to that seen in NASH. The progression from NAFLD to NASH is marked by increased frequency of IL-17+ cells among intrahepatic CD4+ T cells

and a higher Th17/Treg P-type ATPase ratio. Disclosures: The following people have nothing to disclose: Monika Rau, Anne-Kristin Schilling, Ilona Hering, Jan Meertens, Theodor Kudlich, Christian Jurowich, Niklas Beyersdorf, Andreas Geier Background: NASH is increasingly recognized as a disease of lipotoxicity induced by diet and lifestyle. The sequence of events that lead to hepatic lipid accumulation, metabolic changes and mitochondrial dysfunction in NASH are not known. We investigated the chronology of these phenomena in a widely adopted diet-induced animal model of NASH. Methods: Male C57Bl/6 mice were randomly assigned to a fast food (high fat, high cholesterol) or a standard chow (SC) diet and reared up to 36 weeks. Fructose was provided in the drinking water.

(HEPATOLOGY 2011;) Hepatitis C virus (HCV) infects over 3% of the population, causing severe liver disease. Current therapy comprising pegylated interferon (IFN) and ribavirin (Rib) is inadequate, which, combined with high cost and poor patient compliance, has driven the demand for new virus-specific drugs.1 Future standard of care will replace IFN/Rib with combinations of specific inhibitors, such as seen for human immunodeficiency virus (HIV) therapy. However, extensive HCV variability raises concerns FDA approved drug high throughput screening over the ability of relatively few compounds to suppress resistance. Thus, great effort focuses on expanding the repertoire of HCV drug targets, expedited by the availability

of the Japanese fulminant hepatitis clone 1 (JFH-1) infectious isolate.2 HCV is the prototype member of the Hepacivirus genus within the Flaviviridae.3

It is enveloped and possesses a positive-sense single-stranded RNA genome of ∼9.6 kb. An internal ribosome entry site in the 5′ untranslated region drives translation Idasanutlin nmr of a polyprotein that is cleaved into 10 mature products. The core and envelope glycoproteins with the RNA genome comprise the virion, whereas nonstructural (NS) proteins modulate host metabolism and replication of the viral RNA. JFH-1 has permitted the study of particle production, and it has become clear that, in addition to canonical virion components, other viral proteins are required.4-13 HCV p7 forms a cation channel in vitro,14-16 and both deletions and point mutations markedly reduce the production of infectious virions in culture.4, 5 It is comprised of two trans-membrane domains separated by a cytosolic loop and forms both hexameric and heptameric complexes.14, 17, 18 We have recently shown that p7 acts as a proton channel within infected cells, which is directly required for the production heptaminol of infectious virions.19 p7 is required for HCV to replicate in chimpanzees20 and small molecules block both channel function in vitro and virion production in culture, rendering it an attractive antiviral target.21, 22 Skepticism concerning

p7 inhibitors heralds from trials where p7 inhibitor monotherapy, or combinations with IFN/Rib failed to significantly improve responses.23 However, evidence from meta-analyses24, 25 and patient virus loads at early time points26, 27 supports a specific antiviral effect, and selection of specific nonsynonymous mutations occurs within patient isolate p7 sequences.28, 29 Because HCV displays genotype (GT)-dependent p7 inhibitor sensitivity,21 changes in amino acid sequence could interfere with the binding of drug molecules, making it likely that the emergence of resistant quasispecies accounts for trial outcomes. Here, we identify p7 resistance mutations specific to adamantane and IS drugs, indicative of a genuine antiviral effect that supports their inclusion in future combination therapies.

24, 25 Indeed, the Kaplan-Meier analysis shows that patients with HCC who had high p28GANK expression in general had worse prognosis than those with low expression. We believe that p28GANK is an attractive candidate gene for risk prognostication and therapy of HCC. However, our data is apparently at odds with a recent

report suggesting that the cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than those patients with gankyrin-negative HCC.26 The discrepancy may be due to different backgrounds of specimens used, including the buy Afatinib proportion of hepatitis C virus and hepatitis B virus infection, sex of patients, and the classification/criteria of tumor-node-metastasis (TNM) staging. Recently, Ortiz and Tang reported that gankyrin messenger selleck screening library RNA and protein increased in human esophageal squamous cell carcinoma (ESCC) or colorectal cancer (CRC), and its overexpression is poor prognosis of ESCC or CRC due to its significant correlation with TNM stages and metastasis of these tumors, respectively.27, 28 Therefore, p28GANK overexpression may be involved in development of human digestive malignancies such as HCC, ESCC, and CRC. The effect of p28GANK on tumor invasion and metastasis was directly demonstrated in our in vitro and in vivo studies. In both subcutaneous

and orthotopic xenografts, overexpression of p28GANK generated larger primary tumors and more lung metastasis foci, and higher levels of vascularization and angiogenesis, indicating their more aggressive and metastatic properties. Moreover, down-regulation

of p28GANK led to severe suppression of tumor growth and lung metastasis of HCC in mice. To our knowledge, this is the first report that p28GANK expression is critical for HCC metastasis, in addition to tumor proliferation and growth. In this study, we found that TWIST1 is indeed involved in p28GANK-driven EMT. Moreover, p28GANK Celecoxib modulated HIF-1α hyperactivation and expression correlated with TWIST up-regulation and E-cadherin down-regulation. Thus, our data suggest a requirement for HIF-1α in p28GANK-driven EMT. We also observed a role of HIF-1α in p28GANK-regulated VEGF and MMP2 expression, consistent with previous reports that HIF-1α up-regulates VEGF, promoting angiogenesis and invasion of HCC.29–31 Taken together, this study clearly demonstrates a crucial role for p28GANK in induction of EMT and angiogenesis through regulation of HIF-1α, VEGF, and MMP2 expression. An increase in AKT signal is a key tumor survival mechanism, and promotes tumor metastatic processes including EMT, resistance to apoptosis, and angiogenesis.32–34 Previous studies have demonstrated that activated AKT plays a critical role in hematogenous intrahepatic metastasis in an orthotopic implantation model of HCC.35 Our group previously showed a protective role of p28GANK in HCC cells against endoplasmic reticulum stress-induced apoptosis, partially through enhancing AKT phosphorylation.

24, 25 Indeed, the Kaplan-Meier analysis shows that patients with HCC who had high p28GANK expression in general had worse prognosis than those with low expression. We believe that p28GANK is an attractive candidate gene for risk prognostication and therapy of HCC. However, our data is apparently at odds with a recent

report suggesting that the cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than those patients with gankyrin-negative HCC.26 The discrepancy may be due to different backgrounds of specimens used, including the Lumacaftor proportion of hepatitis C virus and hepatitis B virus infection, sex of patients, and the classification/criteria of tumor-node-metastasis (TNM) staging. Recently, Ortiz and Tang reported that gankyrin messenger Ensartinib order RNA and protein increased in human esophageal squamous cell carcinoma (ESCC) or colorectal cancer (CRC), and its overexpression is poor prognosis of ESCC or CRC due to its significant correlation with TNM stages and metastasis of these tumors, respectively.27, 28 Therefore, p28GANK overexpression may be involved in development of human digestive malignancies such as HCC, ESCC, and CRC. The effect of p28GANK on tumor invasion and metastasis was directly demonstrated in our in vitro and in vivo studies. In both subcutaneous

and orthotopic xenografts, overexpression of p28GANK generated larger primary tumors and more lung metastasis foci, and higher levels of vascularization and angiogenesis, indicating their more aggressive and metastatic properties. Moreover, down-regulation

of p28GANK led to severe suppression of tumor growth and lung metastasis of HCC in mice. To our knowledge, this is the first report that p28GANK expression is critical for HCC metastasis, in addition to tumor proliferation and growth. In this study, we found that TWIST1 is indeed involved in p28GANK-driven EMT. Moreover, p28GANK Terminal deoxynucleotidyl transferase modulated HIF-1α hyperactivation and expression correlated with TWIST up-regulation and E-cadherin down-regulation. Thus, our data suggest a requirement for HIF-1α in p28GANK-driven EMT. We also observed a role of HIF-1α in p28GANK-regulated VEGF and MMP2 expression, consistent with previous reports that HIF-1α up-regulates VEGF, promoting angiogenesis and invasion of HCC.29–31 Taken together, this study clearly demonstrates a crucial role for p28GANK in induction of EMT and angiogenesis through regulation of HIF-1α, VEGF, and MMP2 expression. An increase in AKT signal is a key tumor survival mechanism, and promotes tumor metastatic processes including EMT, resistance to apoptosis, and angiogenesis.32–34 Previous studies have demonstrated that activated AKT plays a critical role in hematogenous intrahepatic metastasis in an orthotopic implantation model of HCC.35 Our group previously showed a protective role of p28GANK in HCC cells against endoplasmic reticulum stress-induced apoptosis, partially through enhancing AKT phosphorylation.

As a result, it is difficult to manage hepatic edema using conventional diuretics alone.[6] Tolvaptan is a non-peptide orally available arginine vasopressin V2 receptor antagonist.[7, 8] The drug has been approved for the treatment of hyponatremia in the USA, for the treatment of hyponatremia secondary to syndrome of inappropriate antidiuretic hormone in the EU, and for the treatment of volume

overload in patients with heart failure in Japan.[9] In addition to these indications, add-on therapy of tolvaptan to conventional NVP-BGJ398 mw diuretics is expected to be useful for the treatment of hepatic edema because tolvaptan induces diuresis without sodium excretion.[10] As a series of clinical trials to obtain approval for the additional

indication, a phase 2 dose finding study of tolvaptan in liver cirrhosis patients with ascites were conducted at a low dose of 7.5 mg/day, a middle dose of 15 mg/day (the recommended dose for volume overload in patients with heart failure in Japan) and a high dose of 30 mg/day.[11] Based on the results from the preceding study, a dose of 7.5 mg/day was selected as the optimal dose for liver cirrhosis patients, and a phase 3 study was conducted to confirm the therapeutic effect of tolvaptan as selleck chemical add-on therapy to conventional diuretics at that dose on hepatic edema associated with liver cirrhosis. THIS MULTICENTER, RANDOMIZED, double-blind, placebo-controlled, phase 3 study was conducted at 80 trial sites in Japan between February 2010 and August 2011. This trial consisted of a 3-day pretreatment observation period, a Exoribonuclease 7-day treatment period and a 14-day post-treatment observation period. This trial enrolled liver cirrhosis patients with ascites who had been receiving combination therapies with a loop diuretic and an anti-aldosterone agent from at least 7 days prior to acquisition of informed consent. Standard daily dose of concomitant diuretics in Japan was as follows:

a loop diuretic at a daily dose equivalent to furosemide 40 mg/day or higher and spironolactone at 25 mg/day or higher, or a loop diuretic at a daily dose equivalent to furosemide 20 mg/day or higher and spironolactone at 50 mg/day or higher.[12] Patients, aged 20–80 years, were required to be hospitalized or to be available for hospitalization during the trial period. Main exclusion criteria were hepatic encephalopathy (coma scale, ≥II),[13] vascular invasive hepatocellular carcinoma, requiring new treatment for varices esophageal or gastric varices, hemorrhoidal hemorrhage secondary to rectal varices, and receiving blood products including albumin. This trial was conducted in accordance with ethical principles originating from the Declaration of Helsinki and in compliance with good clinical practice guidelines. The protocol was approved by the institutional review board at each trial site.

Almost 30% of patients living with HIV across Europe do not enter health care until late in the course of their infection. Despite attempts to encourage earlier testing for HIV, this situation has remained stationary for several years without evidence of improvement. Late presentation for care is harmful to the infected person is more costly and is harmful to society. In untreated HIV-infected persons, the risk of developing an AIDS-defining condition increases exponentially as the CD4 cell count drops, being particularly high in those with a CD4 count of 200 cells/ml. The longer therapy is delayed when clinically indicated, the poorer the patient

outcome5. The methodology used in this paper is Existing Data Study (EDS) in the field of HIV and inference from these data to provide a new indicator to assess the HCV progression in community level. Results: This similarity

between GDC-0449 HIV and HCV infections gives a new perspective and also opportunity on the development of indicators which could reliably help us to know how is the quality of Caspase inhibitor treatment and care in CHC patients. Demographic (including age, gender, socioeconomic status and literacy) and epidemiological factors are linked to fibrosis progression in chronic HCV infection3. This makes “presenting liver fibrosis stage”, affected from both host and viral factors, as a new key indicator to evaluate the quality of CHC treatment and care in the population3. “Presenting liver fibrosis stage” indicator in CHC patients, as mentioned above, is composed of, and so affected by, couples of risk factors, both demographically and epidemiologically. This special setting could serve as unique indicator (umbrella indicator or HCV umbrella) to evaluate the population awareness toward the issue of HCV infection, adequacy and timeliness of screening

tests applied in high risk groups, access to medical care and socioeconomic status of people, specially in resource limited settings, to achieve standard of care treatment options regarding high cost of Bumetanide HCV treatment medications. Also, this indicator could be affected by between populations’ cultural differences in terms of life style patterns like alcohol consumption, which is one of important risk factors for fibrosis progression. Suggesting “Presenting liver fibrosis stage“ indicator could be regarded in “individual level”, “community level”, “national level” and “global level”, for comparison of CHC patients’ quality of cares, exactly in the same way that “HIV viral load” is considered as a proxy of incidence in HIV medicine. Also, regarding normal or skewed distribution of fibrosis stages, arithmetic mean or median respectively could be considered as the appropriate central tendency statistics when quantifying or comparing stages of liver fibrosis at community, national or global levels.

Almost 30% of patients living with HIV across Europe do not enter health care until late in the course of their infection. Despite attempts to encourage earlier testing for HIV, this situation has remained stationary for several years without evidence of improvement. Late presentation for care is harmful to the infected person is more costly and is harmful to society. In untreated HIV-infected persons, the risk of developing an AIDS-defining condition increases exponentially as the CD4 cell count drops, being particularly high in those with a CD4 count of 200 cells/ml. The longer therapy is delayed when clinically indicated, the poorer the patient

outcome5. The methodology used in this paper is Existing Data Study (EDS) in the field of HIV and inference from these data to provide a new indicator to assess the HCV progression in community level. Results: This similarity

between click here HIV and HCV infections gives a new perspective and also opportunity on the development of indicators which could reliably help us to know how is the quality of Y-27632 in vivo treatment and care in CHC patients. Demographic (including age, gender, socioeconomic status and literacy) and epidemiological factors are linked to fibrosis progression in chronic HCV infection3. This makes “presenting liver fibrosis stage”, affected from both host and viral factors, as a new key indicator to evaluate the quality of CHC treatment and care in the population3. “Presenting liver fibrosis stage” indicator in CHC patients, as mentioned above, is composed of, and so affected by, couples of risk factors, both demographically and epidemiologically. This special setting could serve as unique indicator (umbrella indicator or HCV umbrella) to evaluate the population awareness toward the issue of HCV infection, adequacy and timeliness of screening

tests applied in high risk groups, access to medical care and socioeconomic status of people, specially in resource limited settings, to achieve standard of care treatment options regarding high cost of Ponatinib datasheet HCV treatment medications. Also, this indicator could be affected by between populations’ cultural differences in terms of life style patterns like alcohol consumption, which is one of important risk factors for fibrosis progression. Suggesting “Presenting liver fibrosis stage“ indicator could be regarded in “individual level”, “community level”, “national level” and “global level”, for comparison of CHC patients’ quality of cares, exactly in the same way that “HIV viral load” is considered as a proxy of incidence in HIV medicine. Also, regarding normal or skewed distribution of fibrosis stages, arithmetic mean or median respectively could be considered as the appropriate central tendency statistics when quantifying or comparing stages of liver fibrosis at community, national or global levels.

Multivariate analysis revealed that AAH expression level was an

independent and significant risk factor affecting recurrence and survival after curative resection, with the greatest HR value for recurrence (HR 3.161, 95% CI 2.115-4.724; P < 0.001,) and the greater value for survival Opaganib research buy (HR 2.712, 95% CI 1.734-4.241; P < 0.001). More importantly, AAH overexpression showed enhanced accuracy in predicting surgical outcome in patients with early stage tumors. Our data suggest that the overexpression of AAH might be an indicator of poor outcome in HCC patients. AAH is a type II transmembrane protein that belongs to the family of α-ketoglutarate–dependent hydroxylases. It specifically hydroxylates the Asp or Asn residue in certain epidermal growth factor–like domains of several proteins,

including Notch and its homologues, Gas6/Axl, laminin, mucin, and other extracellular matrix molecules.14, 29-34 Knockout of AAH in mice leads to developmental defects and an increased incidence of intestinal neoplasia,35 and knockdown of AAH inhibits the migration of NIH-3T3 cells15 and cholangiocarcinoma cells.14 Overexpression of AAH was found in colon cancer, breast cancer, neuroblastoma, pancreatic cancer, and other tumors.14, 36, 37 Recent reports by de la Monte et al.20 and Cantarini et al.21 have shown that the role of AAH in HCC cell motility was associated with activation of the Notch signaling pathway. Moreover, Luu et al.36 reported GDC 0068 that AAH was overexpressed in 10%-28% of patients with different subtypes of non–small

cell lung cancer, and that AAH expression level, tumor size, and clinical stage were independent prognostic factors for survival. Maeda et al.16 reported that AAH overexpression was observed in 46 of 50 patients with intrahepatic this website cholangiocarcinoma, a distinct form of primary hepatic malignancy, and statistically correlated with tumor size, infiltrative growth, aggressive histological grade, vascular invasion, and poor prognosis. The above data support the hypothesis that AAH plays a role in tumor cell invasion in HCC. However, the correlation between AAH expression level and the clinical prognosis of HCC has not been examined. Based on current staging systems, patients with early HCC are thought to be at low risk for recurrence; however, some still have poor prognosis in clinical practice, presenting clinicians with a major challenge in the prognostic prediction of these patients. According to the BCLC staging system, stage A is considered the early stage of HCC. Our results suggest that stage A patients whose tumors have increased expression of AAH could have shorter time to recurrence and survival than those whose tumors had decreased expression of this molecule (Fig. 2C,D).

1. 102±0. 23 in CG, p<0. 05). 〇f note, CTM ileal gene expression of Fgf15 was significantly lower than PG (p<0. 05). Conclusions: We confirmed the occurrence of down-regulation of export and import biliary genes and an upregulation of hepatic Cyp7a1 gene expression during pregnancy in mice. Ileal down-regulation of FGF15 gene expression is likely U0126 datasheet contributory to the observed pregnancy-associated upregulation of Cyp7a1 gene expression

in the liver. In a setting of decreased canalicular export, increased expression of Cyp7a1 may raise bile salt levels inside the hepatocyte and contribute to cholestasis during pregnancy. (FONDECYĪ grant #1110455 to MA). Disclosures: The following people have nothing to disclose: Agustin I. Gonzalez, Tomas I. Rybertt, Juan P. Arab, Margarita Pizarro, Nancy Solis, Marco Arrese Background: Circulating microRNA-122 (miR-122) has been increasingly reported to be a potential biomarker for drug-,

viral-, alcohol- and chemical-induced liver injury. The present study was initiated to determine the potential of circulating miR122 as a biomarker for cholestatic liver injury. Methods: Both bile-duct ligation (BDL) mice and patients with biliary calculi were employed as cholestatic liver injury models, and serum miR-122 level was determined by stem-loop real-time this website reversetranscription PCR (SLqRT-PCR). All quantitative PCR values were normalized to those for U6

RNA and calculated with the 2-ACt method. Results: Serum miR-122 increased significantly after BDL-induced cholestatic injury and showed a similar time course to ALT concentrations. Compared with the sham controls, BDL mice had increased serum levels of miR-122 by 24. 36 ± 12. 86, 423. 63 ± 322. 89, 4. 43 ± 2. 02 and 12. 23 ± 8. 92 folds after 1, 3, 7 and 14 days, respectively. Moreover, serum miR-122 level was substantially higher in patients with biliary calculi than that in the healthy control group. In addition, patients with severe liver injury showed significantly higher levels of serum miR-122 when compared with healthy controls or patients with mild or moderate liver injury. Furthermore, serum miR-122 was found to show significant diagnostic value PRKACG for biliary calculi by yielding an AUC (the areas under the receiver operating characteristic curve) of 0. 931 with 77. 4% sensitivity and 96. 4% specificity in discriminating biliary calculi from healthy controls. Conclusion: Collectively, these data suggest that serum miR-122 has strong potential as a novel, specific and noninvasive biomarker for diagnosis of cholestasis-induced liver injury. Disclosures: The following people have nothing to disclose: Huang S. Feng, Dan N. Wang, Pu Chen, Ping Yang, Cao Ju, Zhang L. Ping “
“von Willebrand factor antigen (vWF-Ag) is elevated in patients with liver cirrhosis, but the clinical significance is unclear.

Blocking BA recycling with LUM001 attenuates these increases and improves tissue morphology suggesting that an ASBTi may provide a novel treatment for cholestatic liver disease that decreases the accumulation of toxic bile acids and reduces the severity of cholestatic liver injury. Disclosures: Bradley T. Keller – Consulting: Shire Human Genetic Therapies Inc; Employment: Lumena Pharmaceuticals,

Rivervest Venture Partners Svetlana Nikoulina – Consulting: Lumena Pharmaceuticals Bronislava Gedulin – Employment: Lumena Pharmaceuticals selleck kinase inhibitor The following people have nothing to disclose: Nicolaus Nazarenkov Although the etiology of primary sclerosing cholangitis (PSC) is unknown and multifactorial, retained bile acids (BA) are likely key drivers of liver injury and fibrosis. Mice deficient in mdr2, a canalicular phospholipid floppase, excrete low phospholipid “toxic” bile causing rapid progression

of Selleck PLX3397 cholestasis and biliary fibrosis resembling small duct PSC. Here we hypothesize that pharmacological inhibition of the ileal apical sodium co-dependent bile acid transporter (ASBT) blocks progression of liver disease in mdr2-/- mice. 30-day-old mdr2-/- mice were fed with high-fat chow containing 0.006% of SC-435, a minimally absorbed, potent inhibitor of ASBT, providing on average 11 mg/kg/day of the compound. 14 days later serum BA and plasma total bilirubin/ ALT levels were determined using enzymatic and colorimetric assays, respectively. Liver histology was assessed blinded on H&E and Sirius Red stained liver sections applying a validated sclerosing cholangitis score. SYBR green and Taqman-based real time RT-PCR was employed to quanti-tate whole liver mRNA expression. Age and gender matched mdr2-/- mice on the same diet without the compound served as controls. Treatment with SC-435 improved animal growth rates (mean±SEM of weight change: +4.3±0.5 vs almost -0.2±0.7 g in SC-435 vs controls; n=6-7 per group, p<0.001) and dramatically reduced plasma biomarkers of cholestasis (total bilirubin: 0.5±0.04 vs 6.8±0.6

mg/dL; p<0.001) and of hepatocellular injury (ALT: 187±22 vs 1358±350 IU/L; p=0.002). On a 1 to 4 scale, liver injury was greatly diminished in the SC-435 treated compared with control mice (grade of inflammation: 1.6±0.3 vs 2.8±0.4, of ductal proliferation 1.4±0.2 vs 3.3±0.2, of necrosis: 1.3±0.2 vs 2.3±0.2, and of fibrosis 1.6±0.2 vs 3.3±0.3; p<0.05 for all parameters). Searching for mechanisms we found that SC-435 caused intestinal bile acid losses, as determined after 7 days of treatment (fecal BA content: 0.35±0.06 vs 0.1 ±0.03 μmol/day in SC-435 vs controls; p=0.01) while dramatically reducing serum BA levels after 14 days (14±2 vs 298±7 μM; p<0.001). Concomitantly, mRNA expression for TNFα, a signature pro-inflammatory cytokine of murine sclerosing cholangitis, was decreased (fold-change over mdr2+/+ mice: 7.1 ±3.6 vs 40±7.2, p=0.02).