17 Prior to treatment initiation, a percentage of the cohort may progress and become ineligible for treatment, or may die; this is dependent upon the timing of treatment initiation. Tofacitinib chemical structure We model the treatment of patients with genotype 1 using telapravir in combination with peginterferon-alfa plus ribavirin; genotypes 2 and 3 are treated with peginterferon-alfa plus ribavirin. Sustained virological response (SVR) rates among patients infected with genotype 1 HCV commencing treatment in fibrosis stages F0-F2 and F3-F4 were 0.78 and 0.62, respectively22; for genotype 2 and 3, SVR rates were 0.76, 0.61, and 0.57

in those treated in fibrosis stages F0-F2, F3, and F4, respectively.23 The MONARCH HCV model is designed to progress a cohort of subjects, in annual cycles, through the Metavir disease stages: F0 (no fibrosis) through F1 (portal fibrosis with no septa), F2 (portal fibrosis with few septa), F3 (portal fibrosis with numerous septa), and F4 (compensated cirrhosis) and potentially on to ESLD complications. The model flow diagram is shown in Fig. 2. Progression through fibrosis stages is controlled via stage-specific transition probabilities

influenced by duration of HCV infection, age, sex, genotype, source of infection (acting as a proxy for post-acquisition behavior), and excessive alcohol consumption (defined as an average daily consumption >20 g).24 Table 1 reports the transition rates and baseline parameters used in the

model. We assumed 75% of chronic HCV infections are genotype 1.17 Subjects enter the model immediately after testing Small molecule library and, in the base case, are distributed across fibrosis stages: (15.0% in F0; 29.5% in F1; 20.3% in F2; 17.1% in F3; 18.1% in F4).17 There are three cohort profiles propagated through the model: 1 Subjects undiagnosed. These subjects progress through the model potentially incurring costs for ESLD complications and health utility decrements associated with ESLD complications. We assumed no costs of chronic HCV were incurred by these individuals. The model assumes no difference in fibrosis stage progression rates between those diagnosed and not diagnosed. The model is run over a lifetime and MCE公司 predicts total costs, QALYs, the number of predicted liver-related complications, and deaths per year. Although our base case analysis focuses on comparing a birth cohort testing and treatment strategy with a risk-based testing and treatment strategy, our primary focus was on the effect of stratifying treatment in those tested by age, fibrosis stage, and time. The model takes a health care payer perspective and considers only direct medical costs; these are presented in Table 2. HCV specific treatment and monitoring costs are derived from weekly estimated costs accommodating duration of treatment; we assume null responders are treated for 12 weeks only. Testing and healthcare costs were estimated from contemporary U.S sources.

Median duration of ETC treatment was 38 months (6-66). Cumulative CVR rates in NA-naïve and experienced patients were 69% vs. 54% at 12th month and 84% vs. 68% at 24th month, 92% vs. 86% at 36th month, respectively (Fig.1, log-rank, p=0.32). 3 patients (10.3%) in NA-experienced group and 4 patients in NA-naïve group (2.2%) required a switch to tenofovir (TDF) due to sub-optimal response to ETC (p=0.061) and 1 NA-naïve patient developed ETC resistance (L180M, M204V, S202G). Multi-variate

logistic regression analysis showed that HBeAg positiv-ity (OR: 6.3, 95% CI 1.16-34.3, p=0.033) and previous LAM experience (OR: 5.8, 95% CI 1.15-29.2, p=0.033) were independent predictors for a requirement NVP-LDE225 to switch to TDF. Conclusion: ETC has a potent antiviral efficacy in patients with CHB. The antiviral efficacy of ETC is not influenced by prior treatment with NAs if LAM resistance is excluded at baseline. However, HBV-DNA kinetics should be carefully monitored in patients with HBeAg-positive CHB and previous LAM experience. Disclosures: The following people have nothing to

disclose: Bulent Baran, Rapamycin Ozlem Mutluay Soyer, Asli Cifcibasi Ormeci, Suut Gokturk, Sami Evirgen, Filiz Akyuz, Cetin Karaca, Kadir Demir, Fatih Besisik, Derya Onel, Mine Gulluoglu, Selim Badur, Sabahattin Kaymakoglu Background: Chronic hepatitis B (CHB) disproportionately affects Asian-Americans in the US. TDF has been demonstrated potent antiviral in clinical trials, but real-life data in Asian-Americans are lacking. We prospectively followed patients on TDF for 144 weeks and assessed outcomes. Methods: Asian-American patients with CHB from multiple community-based practices were prospectively enrolled and treated with TDF (300 mg/day) in a single arm study for 48 weeks. After week 48, patients had the option to continue TDF up to week 144, or opt out of further observation. The primary efficacy endpoint was hepatitis B virus (HBV) DNA < 29 IU/mL at week 48 MCE公司 and 144. Secondary endpoints were safety and tolerability, serologic and biochemical

responses, liver fibrosis by FibroTest at week 48, and the development of drug resistant mutations. Results: Ninety patients were enrolled with baseline values in Table 1. At week 48, seventy four patients (82% overall; 70% HBeAg-positive and 100% HBeAg-negative) had HBV DNA <29 IU/mL. 12% (6/52) HBeAg+ patients achieved HBeAg loss/seroconversion. The percentage of patients with alanine aminotransferase (ALT) in the normal range increased from 26% at baseline to 66% at week 48. The percentage of patients with F0 fibrosis by FibroTest increased from 48% to 51%, and those with F4 fibrosis decreased from 4% to 1 %. At week 48, 31 /90 patients (19 HBeAg+) opted to continue on TDF with assessment at 12 week intervals up to week 144. Two patients with HBV viremia did not participate beyond week 48. At week 144, 84% (26/31) patients had HBV DNA <29 IU/mL; No viremic patient (n=5) had genotypic mutation on Sanger sequencing (2/5 TDF non-adherence); 67.

Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma

and haemarthrosis. SCBT administration alternated one APCC dose to 1–3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20–80 U kg−1) was given every 8–12 h; rFVIIa (90–270 μg kg−1) was given every 3–12 h. Bleeding control was achieved in 12–24 h in all patients. SCBT was discontinued after 1–15 days. Selleckchem RGFP966 No clinical adverse events were observed, but a significant increase in D-dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A MK-1775 ic50 prospective clinical trial is needed to provide further evidence. “
“Summary.  Wound healing involves a complex series of interactions between coagulation, inflammation, angiogenesis, and cellular migration and proliferation. Our laboratory has developed an excisional dermal wound model in mice in order to study some of these processes and to determine how coagulation defects affect wound healing. In contrast to wild type mice, haemophilia B mice typically show delayed healing, signs of bleeding into the wound, and significant wound expansion. The difference in wound size may result from limited fibrin deposition in haemophilic animals and the subsequent inability to anchor the platelet plug to the surrounding tissues, thus allowing

wound expansion through oedema. Haemophilic mice also demonstrate impaired wound healing times. However, while pre-treatment with factor IX or human activated factor VII improves

some wound characteristics in haemophilia B animals, the time to wound healing is still delayed and signs of ongoing bleeding are evident. Haemophilic mice also show a deficient initial inflammatory response and increased angiogenesis, medchemexpress which, in turn, leads to increased bleeding: in the absence of robust haemostasis, these fragile, newly sprouted vessels have a tendency to bleed. Taken together, these observations suggest that ongoing haemostasis is necessary for normal wound healing. If this is correct, then optimal wound healing in haemophilia would require therapy until at least the point that vessel formation is stabilized. The goal of such treatment would be to avoid a feedback cycle in which bleeding tends to lead to further bleeding. Once initiated, this cycle may be difficult to control. “
“Summary.  Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques.

Nagorney, MD Session II: Adenoma 3:50 – 4:10 PM Imaging Characteristics of Adenomas BachirTaouli, MD 4:10 – 4:30 PM How Molecular and Immunohistochemical Analyses Can Help Us Guide Therapy For Hepatic Adenomas and FNH Jessica Zucman-Rossi, MD, PhD 4:30 – 4:50

PM Resection, Transplantation and Local Regional Therapies For Adenomas Jacques Belghiti, MD 4:50 – 5:10 PM Break Session III: Neuroendocrine Tumors 5:10 – 5:30 PM Imaging Characteristics of Neuroendocrine Tumors Bachir Taouli, MD this website 5:30 – 5:50 PM Current NANETS and ENETS Guidelines for Management Of Neuroendocrine Tumors Diane Reidy, MD 5:50 – 6:10 PM Liver Transplantation for Neuroendocrine Tumors Vincenzo Mazzaferro, MD 6:10 – 6:30 PM Liver Resection and Local Regional Therapies for Neuroendocrine Tumors Timothy M. Pawlik, MD, PhD 6:30 – 6:40 PM Debate: Patients with Neuroendocrine Tumors Will Do Well No Matter What We Do – So Why Treat Them? Vincenzo Mazzaferro, MD 6:40 – 6:50

PM Debate: Patients with Neuroendocrine Tumor Will Do Better With Aggressive Treatment Timothy M. Pawlik, MD, PhD 6:50 – 7:00 PM Closing Remarks AASLD BUSINESS MEETING (MEMBERS ONLY) Saturday, selleck chemicals November 2 5:15 – 6:15 PM Hall E – General Session Room J. Gregory Fiz, MD, presiding Early Morning Workshops Sunday, November 3 6:45 – 7:45 AM Refer to your luncheon ticket for meeting room location. Sunday Basic Early Morning Workshops Goals and Objectives: Bring together investigators in a specific area of research to discuss their ongoing work. Focus of discussions is on new work and not a review of previous studies. Allow ample time for questions from the audience. EMW-1 Artificial Liver Support Systems Jayanta Roy-Chowdhury, MD and Vicente Arroyo, EMW-2 HCV Replication Andrew H. Talal, MD and Raymond T.

Chung, MD EMW-3 Triggers of Fibrosis in NASH Ariel E. Feldstein, MD and Detlef Schuppan, MD, PhD EMW-4 Cholangiocyte Pathobiology Gianfranco Alpini, PhD and Marco Marzioni, MD EMW-5 Microbiome and the Liver Bernd Schnabl, MD and David Brenner, MD EMW-6 Animal Models of NAFLD Rohit Kohli, MD and Michael R. Charlton, MD 上海皓元 Sunday Clinical Early Morning Workshops Goals and Objectives: Discuss difficult management issues utilizing acknowledged experts in the area. Provide an overview of the current state-of-the-art in each area. Allow ample time for questions from the audience. EMW-7 Imaging of Liver Tumors Claude B. Sirlin, MD and Laura M. Kulik, MD EMW-8 Liver Transplantation for Hepatitis C Xavier Forns, MD and Norah Terrault, MD EMW-9 New Anti-Tumor Agents in Development for HCC Jorge A. Marrero, MD and Josep M.

[2] To confirm and extend this observation we investigated STAT3 activation in the presence of HCV replication in the context of a HCV genomic replicon and the complete HCV life cycle (JFH-1). STAT3 activation requires posttranslational modifications

through phosphorylation at tyrosine 705 (Y705) to be functionally active. Phosphorylation at this Y705 residue results in STAT3 dimerization and translocation to the nucleus. In the presence of both the genomic replicon (Fig. 1A) and JFH-1 infection (Fig. 1B), levels BMS-907351 mw of STAT3-Y705 phosphorylation were significantly increased in the presence of HCV, in comparison to uninfected Huh-7 cells, as shown by specific detection of STAT3-Y705 by immunoblot and quantification by densitometry analysis. The presence of replicating HCV

did not seem to alter total STAT3 protein within Huh-7 cells, suggesting that HCV replication does not significantly impact basal STAT3 expression (Fig. 1A,B). We next sought to determine if this HCV-dependent increase in STAT3-Y705 phosphorylation corresponded to a concomitant increase in functional STAT3 transcriptional activity. Huh-7.5 cells infected with HCV JFH-1 (48 hours) and HCV genomic replicon cells were transiently transfected with a plasmid containing a STAT3-responsive DNA element driving luciferase (pSTAT3-luc). Luciferase results were expressed as a fold change relative to the control cells (no HCV medchemexpress replication). HCV genomic replicon (Fig. 1C) and JFH-1 (Fig. 1D) replication significantly enhanced STAT3 Neratinib luciferase output. This indicates that HCV replication induces activation of STAT3 by way of increased STAT3-Y705 phosphorylation, correlating with enhanced STAT3 transcriptional activation.

Collectively, these results demonstrate that HCV replication drives activation of functional STAT3. To investigate if STAT3 activation affects the HCV life cycle, we expressed a constitutively active STAT3 molecule (PRc/CMV-STAT3-C) in Huh-7 cells harboring HCV replication. STAT3-C is a constitutively active form of STAT3 in which two cysteine residues inserted into the C-terminal loop of STAT3 allows for the formation of disulfide bonds between STAT3 monomers resulting in the formation of active STAT3 homodimers.[17] Transient expression of STAT3-C (48 hours) resulted in a significant increase in STAT3-dependent luciferase output, indicating that this construct is functional and active in our system (Supporting Fig. 1). We then sought to express STAT3-C both transiently and stably in the context of JFH-1 infection. Transient expression of STAT3-C, followed by infection with JFH-1 (MOI = 0.01) for 24 hours resulted in a significant 2-fold increase in HCV replication (Fig. 2A). These results were then substantiated using Huh-7.5 cells stably expressing STAT3-C (Fig. 2B).

Also, the addition of precore A1896 mutants and basal core promoter T1762/A1764 mutants would have identified 98.5–100% of these patients. Conclusion:  The updated treatment guidelines for hepatitis B still excluded patients who developed serious liver-related complications. The inclusion of baseline serum albumin and platelet counts to current criteria would have identified a majority of these patients for antiviral therapy. These tests should be included into hepatitis B treatment strategies. “
“Hepatitis B (HB) vaccination is highly effective to reduce the risks of hepatitis B virus (HBV) infection. However, breakthrough and chronic

HBV infections in vaccinated subjects raised concern about its’ long-term efficacy. The specific OTX015 solubility dmso aim of the study PD0332991 molecular weight was to explore host genetic determinants of long-term immunological memory against HB vaccination. We conducted a case-control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers≧10 mIU/mL at age of 15-18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes

and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques. We found that 10 of the 112 candidate SNPs (p-value <5.0×10-5) clustered within a 47 Kb region of the HLA-DP loci. All the minor alleles of these HLA-DP candidate SNPs were correlated with lower likelihoods of non-response to HB vaccine. There were significant linkage disequilibrium between these HLA-DP candidate SNPs and HLA-DPB1 protective alleles. Multivariate analyses showed that rs7770370 was the most significant genetic factor. As compared with rs7770370 GG homozygotes, adjusted odds ratios were

0.524 (95% confidence 上海皓元 interval [CI], 0.276-0.993) and 0.095 (95% CI, 0.030-0.307) for AG heterozygotes and AA homozygotes, respectively. Our results showed that rs7770370 was the most significant genetic factor of response to HB booster. The rs7770370 and nearby SNPs may also contribute to the long-term immunological memory against HB vaccination. “
“Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the management of patients infected with human immunodeficiency virus (HIV), increases medical costs, alters the prescription patterns, and affects the guideline recommendations. Among the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reactions and lactic acidosis are recognized as acute events with potential to evolve into fatal cases, whereas there seems to be other syndromes not as well characterized but of equal concern as possible long-term liver complications.

5-HT7 receptor expression was determined by Real Time PCR. Routine histopathology and immunhistochemical staining for TNF-a were also performed in liver sections. Potential role of 5-HT7 receptors were investigated by administration of LP44 (5-HT7 receptor agonist) and SB269970 (5-HT7 receptor antagonist) at two different doses. Results: At 4th, 8th and 12th hours after PARA administration, AST and

ALT were significantly increased and GSH was significantly decreased when compared to control. Agonist administration to PARA selleck chemical given rats significantly improved liver conditions in terms of AST, ALT, GSH and TNF-α. However antagonist administration worsened liver functions, those results were also supported histopathological and immunohistochemical analyses. Real Time PCR results showed that liver 5-HT7 receptor expression decreased in a time dependent manner after PARA administration. Agonist administration increased 5-HT7 receptor expression back in all time points while antagonist had no effect. Conclusions: In conclusion, this study demonstrated for the first time that 5-HT7 receptor expression

in liver tissue is decreased during PARA induced hepatotoxicity. Agonist administration can be a new therapeutic approach for PARA induced liver damage. Also 5-HT7 receptors may be a promising new therapeutic target selleckchem for prevention of drug and other chemicals induced hepatotoxicity. This study may MCE公司 also provide a new glimpse into drug induced hepatic damage’s pathophysiology. Disclosures: Beyzagul Polat – Grant/Research Support: TUBITAK Emre Karakus – Grant/Research Support: TUBITAK The following people have nothing to disclose: Zekai Halici, Elif Cadirci, Yasin Bayir, Abdulmecit Albayrak, Deniz Unal Although the progression of alcoholic liver disease is well-described, the mechanisms leading to alcohol-induced liver

damage remain elusive. Previously, we determined that microtubules are hyperacetylated and more stable in ethanol-treated WIF-B cells, liver slices and in livers from ethanol-fed rats. Our focus is to determine whether tubulin hyperacetylation can explain alcohol-induced defects in microtubule-dependent protein trafficking. Previously, we determined that transport of newly synthesized proteins from the Golgi to the basolateral surface and STAT5B nuclear translocation are impaired by alcohol metabolism. Recently, we confirmed that delivery of apical proteins from the basolateral-to-apical membrane via transcytosis is also impaired in ethanol-treated WIF-B cells. Similar to STAT5B nuclear translocation, transcytosis is mediated by dynein (a minus-end directed motor) and dynactin (a dynein activating complex). Unlike control cells, transcytosing proteins accumulated sub-apically and aligned along acetylated microtubules in ethanol-treated cells indicating that impairment was due to vesicle translocation, not basolateral internalization.

21 This conversion is catalyzed by the acetyl-coA synthetases,22 recently redesignated acyl-coenzyme A synthetase short-chain family members 1 and 2 (ACSS1 [UniProt Q9NUB1] and ACSS2 [Q9NR19]).23 The role of acetyl-coA synthesis in control of inflammation has not previously been investigated and could open

click here a novel field of study into the relationship between cellular energy supply and inflammatory disease. In this study we test the hypothesis that ethanol enhances macrophage cytokine production by uncoupling gene transcription from its normal regulatory mechanisms through increased histone acetylation, and that the conversion of the ethanol metabolite acetate to acetyl-coA is crucial to this process. AAH, acute alcoholic hepatitis; ACSS, acyl-coenzyme A synthetase short-chain; ALD, alcoholic liver disease; ER, endoplasmic reticulum; HAT, histone acetyltransferase; HDAC, histone deacetylase; IL, interleukin; LPS, lipopolysaccharide; NAD, nicotinamide adenine dinucleotide;

ROS, reactive oxygen species; SIRT, sirtuin; SREBP, sterol response element binding protein; TLR, Toll-like receptor; TNF, tumor necrosis factor. The human monoblastic cell line MonoMac6 (DSMZ, Braunschweig, Trichostatin A Germany, ACC124), an established human cell line that displays features of mature macrophages and has been used to model Kupffer cell responses in ethanol,10 was grown in RPMI-1640 上海皓元 medium supplemented with 2 mM l-glutamine (Lonza, Basel, Switzerland), 1 mM sodium pyruvate, 1× nonessential amino acids (both Gibco, Paisley, UK), 10% fetal calf serum (Lonza), and 9 μg/mL human insulin (Sigma, St. Louis, MO). Ethanol exposure was achieved in fresh media with 86 mM (0.5%, 400 mg/dL) ethanol (VWR, Poole, UK). This is five times the legal blood alcohol limit for driving in the UK and equivalent to heavy drinking in humans.24 The ethanol concentration

was maintained by using ethanol vapor in the incubator to prevent evaporation of ethanol from culture media10 and monitored by potassium dichromate reduction assay (BioAssay Systems, Hayward, CA). For acetate culture experiments, media were supplemented with 1 mM sodium acetate (Sigma) and replaced every 48 hours to minimize fluctuations in acetate concentration. One mM is an achievable acetate concentration in an individual metabolizing ethanol at the concentration used.25 After 7 days incubation cells were resuspended in fresh medium at 2 × 106/mL and stimulated with E. coli O111:B4 LPS (InvivoGen) at a final concentration of 10 ng/mL.

Other observational studies focussed on behaviours such as dyadic agonistic interactions with low and high intensity

levels in bats Megaderma lyra (Bastian & Schmidt, 2008), mother–pup interactions characterized by different levels of valence and arousal (reunion, separation, nursing) in Weddell seals Leptonychotes weddellii (Collins et al., 2011) or infant restraint by female rhesus monkeys Macaca mulatta characterized by different threat severity levels (Jovanovic & Gouzoules, 2001). Several studies also recorded naturally occurring or experimentally Palbociclib chemical structure elicited alarm calls, which have often

been shown to simultaneously communicate the type of predator and the level of urgency (i.e. both referential and emotional information, see Manser, Seyfarth & Cheney, 2002; Seyfarth & Cheney, 2003 for a review). Studies conducted in laboratories or on farms usually consist in placing the animals in various situations characterized by different levels of arousal or valence (method = ‘Experimental’ in Table 3). Most commonly, one or several types of vocalizations are recorded during complete or partial isolation or separation from conspecifics (e.g. Schrader & Todt, 1993; Byrne & Suomi, 1999; Norcross & Newman, http://www.selleckchem.com/products/chir-99021-ct99021-hcl.html 1999; Norcross, Newman & Cofrancesco, 1999; 上海皓元 Yamaguchi, Izumi & Nakamura, 2010; Siebert et al., 2011; Sèbe et al., 2012), during human approach tests (e.g. Marchant et al., 2001; Gogoleva et al., 2010a , b ) or during routine farm and industry-wide procedures (e.g. castration, branding; Weary et al., 1998; Watts & Stookey, 1999; von Borell et al., 2009). Few studies examined the relationship between vocal parameters and physiological indicators of stress (i.e. cortisol

or adrenaline levels, cardiac activity; Byrne & Suomi, 1999; Norcross & Newman, 1999; Marchant et al., 2001; Sèbe et al., 2012). Positive vocalizations in studies investigating valence were elicited by the following situations; grooming by an experimenter (Scheumann et al., 2007), friendly approach by a caretaker (Yeon et al., 2011), playing (Yin & McCowan, 2004; Taylor et al., 2009), feeding time (Pond et al., 2010) and finally in response to a familiar companion or by activating the ascending dopaminergic system (Brudzynski, 2007). Fifty-four of the 58 studies included in Table 3 investigated the effect of arousal on vocal parameters, making the shifts for arousal presented in Table 4 reliable.

Compared to mice with HBV alone, significant reductions in serum levels of HBV-DNA, HBsAg and HBeAg occurred in the FK228 order NAFLD + HBV group after 24 weeks (all P < 0.05). Nevertheless, the NAFLD and NAFLD + HBV groups shared comparable

physical and metabolic disorders and similar steatotic, inflammatory and fibrotic characteristics in the liver. High-fat diets and transgenic operations on the HBV genotype B induced a rodent model of NAFLD overlapping with chronic HBV infection, and this model reduces the HBV viral factors but not the metabolic and histologic features. “
“The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important transcriptional regulator of liver selleck inhibitor metabolism. Despite recent advances in understanding its functions,

how FXR regulates genomic targets and whether the transcriptional regulation by FXR is altered in obesity remain largely unknown. Here, we analyzed hepatic genome-wide binding sites of FXR in healthy and dietary obese mice by chromatin immunoprecipitation sequencing (ChIP-seq) analysis. A total of 15,263 and 5,272 FXR binding sites were identified in livers of healthy and obese mice, respectively, after a short 1-hour treatment with the synthetic FXR agonist, GW4064. Of these sites, 7,440 and 2,344 were detected uniquely in healthy and obese mice. FXR-binding sites were localized mostly in intergenic and intron regions at an inverted repeat 1 motif in both groups, but also clustered within 1 kilobase of transcription start sites. FXR-binding sites were detected near previously unknown target genes with novel functions, including

diverse cellular signaling pathways, apoptosis, autophagy, hypoxia, inflammation, RNA processing, metabolism of amino acids, and transcriptional regulators. Further analyses of randomly selected genes from both healthy and obese mice suggested that more FXR-binding sites are likely functionally inactive in obesity. Surprisingly, occupancies of FXR, retinoid X receptor alpha, RNA polymerase II, and epigenetic gene activation and repression histone marks, and messenger RNA levels of genes examined, suggested that direct gene repression by agonist-activated FXR is common. Conclusion: Comparison of genomic FXR-binding sites in healthy and obese MCE公司 mice suggested that FXR transcriptional signaling is altered in dietary obese mice, which may underlie aberrant metabolism and liver function in obesity. (HEPATOLOGY 2012;56:108–117) Farnesoid X receptor (FXR, NR1H4) belongs to the nuclear receptor superfamily.1-3 As the primary biosensor for endogenous bile acids, FXR plays a crucial role in maintaining bile acid homeostasis by regulating the expression of numerous genes involved in bile acid metabolic pathways, including biosynthesis and transport of bile acids mainly in the liver and intestine.