Mullen this website – Advisory Committees or Review Panels: GILEAD; Speaking and Teaching: GILEAD Andrea D. Branch – Grant/Research Support:

Kadmon, Gilead, Janssen Damaris C. Carriero – Consulting: Genentech, Gilead, Vertex; Speaking and Teaching: Genentech, Vertex The following people have nothing to disclose: Daniel S. Fierer, Alison J. Uriel, Wouter O. van Seggelen, Rosanne M. Hijdra, David Cassagnol BACKGROUND: Since 2011 recommended treatment for HCV genotype 1 has been pegIFN/RBV combined with TVR or BOC. However, adherence to current response guided therapy (RGT) and the effectiveness of triple therapy outside of registration trials are poorly defined. AIMS: To assess utilization of RGT and virologic responses for a large cohort of pts treated within the U. S. based upon local practice and HCV RNA determinations. METHODS: HCV-TARGET is an ongoing longitudinal observational study at 44 academic and 59 community centers. Demographic, clinical and virologic data and adverse events are collected throughout treatment and follow-up on sequentially enrolled pts, together with information on adherence to treatment futility rules at key time points. RESULTS: Of 2,212 GW-572016 in vivo pts enrolled

in TARGET, 709 have been followed for at least 1 yr, of whom 524 had a determination of virologic outcome within a window up to 6 wks after stopping therapy (SVR6). Of 524 pts, 61% were male, 77% Caucasian (17% Black). Their mean age was 56 yrs (range 18-76), 41% were treatment naive and 44% cirrhotic. Adherence to futility rules was evaluated: an HCV RNA result was available at wk 4 in 84% of pts on TVR and in 73% of pts on BOC by wk 12.Among pts on TVR, 19/457

(4%) had HCV RNA >1000 IU at treatment wk 4; 7 (37%) promptly discontinued treatment, 9 (47%) discontinued later (mean medchemexpress −7.8 wks) but 3 remained on treatment and 1 achieved SVR6.Of pts with a planned BOC regimen, 12 had an inadequate viral response to pegIFN/RBV by wk 4 so treatment was discontinued. By wk 8, HCV RNA declined <3 log10 from baseline in 12/142 (8%) on BOC; 5 (42%) promptly discontinued treatment, while 7 (68%) continued. By wk 12 on BOC, 16/123 (13%) met the futility rule (residual HCV RNA >100 IU). Of these, 7 (58%) stopped therapy within 2 wks, 6 continued (mean +5.5 wks; range 3-12 wks), 3 completed a full course of treatment, although only 1 achieved SVR6.Table shows rates of SVR6.CONCLUSIONS: RGT virologic milestones appeared to be managed appropriately in most pts. Preliminary SVR results were lower than in published pivotal studies, possibly because pts in this large cohort had difficult-totreat characteristics (cirrhosis, genotype 1a, prior null response).

Indices of neutrophil phenotype and function were examined with respect to severity and nature of Small molecule library liver injury, severity of organ failure, liver prognostic

criteria of survival, and eventual outcome. The relationship between plasma-derived factors and neutrophil function was also examined in order to aid identification of other associated biomarkers in ALF. AALF, acetaminophen-induced liver failure; ALF, acute liver failure; APACHE, acute physiology and chronic health evaluation; CARS, compensatory antiinflammatory response syndrome; fMLP, formyl-Met-Leu-Phe; ICU, intensive care unit; IQR, interquartile range; LT, liver transplantation; MAP, mean arterial blood pressure; MELD, model for endstage liver disease; MFI, mean fluorescence intensity; NPA, neutrophil phagocytic activity; OB, oxidative burst; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; SALF, subacute liver failure; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment. A

cross-sectional case-control cohort study was performed. Patients with ALF (n = 15) and subacute liver failure (SALF) (n = 10) were prospectively studied. Neutrophil phenotype, NPA, and OB (spontaneous and stimulated with opsonized E. coli) were determined and compared Sotrastaurin solubility dmso to n = 11 HC and n = 6 SC. The dynamics of neutrophil function during the course of the illness were compared between patient groups and in relation to those who survived compared to those who did not survive. Patients who were transplanted were considered nonsurvivors. Baseline sampling was performed within 24 hours of admission to an intensive care (ICU) and every 3-4 days until spontaneous recovery, death, or LT. In those who underwent LT further sampling was performed 72 hours post-LT. Subjects were followed up for 90 days. Twenty-five patients with ALF or SALF were recruited nonconsecutively

on admission MCE to the liver ICU at King’s College Hospital between October 2008 and August 2010. ALF was defined by the onset of hepatocellular dysfunction in the absence of preexisting liver disease characterized by coagulopathy and encephalopathy and an illness of less than 26 weeks duration. ALF was further subclassified according to the criteria defined by O’Grady et al.15 depending on the time between the onset of jaundice and encephalopathy. (1) Hyperacute (jaundice to encephalopathy time <7 days) consisting predominantly of patients with acetaminophen-induced liver failure (AALF). (2) Acute liver failure (jaundice to encephalopathy time 8-28 days) typified by patients presenting with fulminant viral hepatitis. (3) SALF (jaundice to encephalopathy time 5-12 weeks) typified by those presenting with nonacetaminophen drug-induced liver injury and seronegative/acute autoimmune hepatitis. Patients with ALF/SALF were included if they were age >18 years and <80 years.

Bicarbonate was determined in bile with a Beckman Synchron CX3 analyzer (Beckman, Albertville, MN). NO and NO in bile and cell supernatants were measured with a nitrate/nitrite colorimetric assay kit from Cayman Chemical (Ann Arbor, MI). The hepatic glutathione concentration was quantified with a commercial kit from Sigma, and the total NOS activity in liver tissue was measured with a radioactivity-based NOS activity assay kit from Cayman Chemical. The protein concentration in samples was determined according to Bradford’s method.20 Total SNOs and low-molecular-weight nitrosothiols (LMw-SNOs) were measured in bile with 4,5-diaminofluorescein MK1775 (Calbiochem).21

This compound (10 μL) was added to 1-mL diluted bile samples (200 μL in phosphate-buffered saline with or without 0.2% HgCl2). After 10 minutes of incubation at room temperature, fluorescence was measured at an excitation wavelength of 495 nm and an emission wavelength of 515 nm. The SNO content (FSNO) was estimated as the difference between the fluorescence measured in the presence of HgCl2 (F1) and the fluorescence measured in its absence (F2; i.e., FSNO = F1 − F2). In addition, 300-μL bile samples were filtered with Centricon devices with a molecular weight cutoff of 10 kDa (Millipore,

Billerica, MA), and the LMw-SNO content was measured in the filtrate as described previously. To characterize Lumacaftor biliary glutathione and GSNO, MS analysis was performed after protein precipitation via the mixing of a 500-μL sample with an equal volume of 98% acetonitrile and 0.2%

formic medchemexpress acid. After 30 minutes of incubation on ice, samples were centrifuged at 4000g. Supernatants were then infused with a 100-μL syringe connected to a Q-TOF Micro instrument (Waters, Milford, MA) through a PicoTip nanospray ionization source (Waters). The heated capillary temperature was 80°C, and the spray voltage was 1.8 to 2.2 kV. MS data were collected and processed with Masslynx 4.1 (Waters). Homogenates from liver samples, common bile ducts, and NRCs were subjected to western blot analysis as described22 with antibodies against iNOS (Santa Cruz Biotechnology, Santa Cruz, CA), Akt, or phosphorylated Akt (Ser473; Cell Signaling, Beverly, MA). For a loading control, a β-actin antibody (Sigma) was employed. Results are expressed as means and standard errors of the mean. Comparisons of quantitative variables among groups were made with analysis of variance or Kruskal-Wallis tests (followed by the Student t test or Mann-Whitney nonparametric test, respectively), as required. A P value < 0.05 was considered to be significant. UDCA administration through the femoral vein in anesthetized rats with a cannulated common bile duct (i.e., the isPRL model) induced a dose-related increase in both the biliary total amount (Fig. 1A) and the concentration (data not shown) of the NO-breakdown products NO and NO, and this reflected increased biliary NO secretion (Fig. 1A).

All three PPAR isotypes exhibit anti-inflammatory effects.[7] Therefore, modulation of the activation of these transcription factors, which are misregulated in NAFLD/NASH,[8] is perfectly suited as a therapeutic approach to control inflammatory and metabolic signaling in NAFLD/NASH, as has been previously delineated.[9] Available data indicate that PPAR-α activation with synthetic ligands (fibrates) selleck products is able to abolish steatosis and reduce fatty liver in rodents, but has limited effects in humans.[10] On the other hand, PPAR-γ ligands (thiazolidinediones) have demonstrated to be effective in reducing liver fat content, decreasing serum levels of aminotransferases,

and also ameliorating steatosis, inflammation, and even fibrosis in patients

with NAFLD/NASH.[1] However, drugs in this class are associated with undesirable side effects, such as fluid retention and decreased bone mass, and some concerns regarding long-term safety have recently emerged. In particular, data indicate that rosiglitazone may increase the risk for cardiovascular events, and pioglitazone selleck chemicals llc possibly increases the risk of bladder cancer.[11] Finally, because PPAR-δ activation reduces fat burden in liver cells and modulates hepatic inflammation and fibrosis in animal models,[12, 13] targeting this receptor could be of benefit for patients with NAFLD. Clinical studies with PPAR-δ agonists in moderately obese men, patients meeting diagnostic criteria for metabolic syndrome (MetS), or patients with dyslipidemia, most of them likely suffering from NAFLD, are promising in this regard,[13] but available data are limited. Efforts to develop new agents that simultaneously combine the beneficial effects of agonizing

different PPARs (dual PPAR-α/γ, -α/δ, or -γ/δ agonists or even panagonists α/δ/γ) have been made.[14] Indeed, these multimodal drugs represent an attractive class of agents with therapeutic potential for T2DM, MetS, dyslipidemia, and, likely, NAFLD/NASH. Several dual PPAR-α/γ 上海皓元 agonists have been tested in recent years, but a number of safety concerns raised questions about their clinical applications. PPAR-α/δ agonist have been developed more recently, with GFT505 being a first-in-class agent. The work by Staels et al.[5] is the first preclinical study assessing the efficacy of the dual PPAR-α/δ agonist, GFT505, in mouse models of NAFLD/NASH. The investigators first explored the pharmacokinetics of the compound in rats, showing that GFT505 undergoes extensive enterohepatic cycling. This is interesting because it implies that the drug acts mainly in the liver with limited effects in peripheral organs and potential safety implications.

In each SNP study, between 50 and 117 subjects of each group were randomly selected for participation. The following Epigenetics Compound Library cell line SNP from nine positions in seven candidate genes were tested: tumor necrosis factor-alpha (TNF-α) -308 and -238, adiponectin -45 and -276, leptin -2548, peroxisome proliferator-activated receptors-γ (PPAR-γ) -161, peroxisome proliferator-activated receptors-γ

co-activator-1α (PGC-1α) -482, hepatic lipase -514 and phosphatidyletha-nolamine N-methyltransferase (PEMT)-175. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. SNP were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. The genetic polymorphisms were separated on 3% agarose gel electrophoresis and visualized under ultraviolet (UV) light

after ethidium bromide staining. The data were analyzed using SPSS Alectinib 12.0 (Chicago, IL, USA). Continuous data were expressed as mean ± standard deviation and examined using the Student’s t-test. Categorical variables were expressed as a percentage and examined using the χ2-tests and Fisher’s tests. Statistical significance was set at P < 0.05 (two-tailed). Stratified analyses with gender as subgroups were carried out when differences between case and control groups did not reach significance. This study complied with the 1975 Declaration of Helsinki and was approved by the Ethics Committee MCE of Guangzhou Medical College. Written consent was obtained from each participant. Most parameters related to metabolic syndrome were significantly different between the NAFLD and control groups. In this study, almost all NAFLD subjects

(109/117, 93.2%) diagnosed with ultrasonography were overweight (i.e. BMI ≥ 23 but <25) or obese (BMI ≥ 25) according to the Asian criteria.17 At promoter region -308 of the TNF-α gene, there was no significant difference in the genotypic distributions and the allelic frequency between the NAFLD and control groups (P > 0.05). However, at position -238, the differences were statistically significant (P < 0.05). Our results suggest that the G/A variant at the TNF-α gene -238 increased susceptibility to NAFLD and that the variant at -308 was not relevant. Gender-level analysis showed no significant difference (P > 0.05). At exon 2 of adiponectin gene -45, genotypic distributions were significantly different between the NAFLD and control groups (P < 0.05), but the difference in allelic frequencies was not (P > 0.05). Both the genotypic distributions and allelic frequencies of adiponectin gene -276 were significantly different between the NAFLD and control groups (P < 0.05). These results suggest that the T/G variant at adiponectin gene -45 was weakly positively associated with susceptibility to NAFLD, but that the G/T variant at -276 may decrease susceptibility. There was no significant gender difference between groups.

112,113 In a large retrospective tertiary center study, Tack et al.114 showed that a subset of presumed post-infectious dyspepsia patients had higher prevalence of impaired accommodation of the proximal stomach. There is evidence that post-infectious FD can occur in a subset of patients, and functional selleck inhibitor abnormalities and persistent inflammation of the gut are found. Statement 20. Genetic factors may be involved in pathogenesis in a subset of patients with functional dyspepsia. Grade of evidence: low. Level of agreement: a: 78.9%; b: 15.8%; c: 5.3%; d: 0%; e: 0%; f: 0%. The G-protein β3 subunit C825T polymorphism was reported to be associated with dyspepsia in studies from the United States (both

CC and TT genotypes with meal-unrelated dyspepsia)115 and Germany (CC genotype).116 In contrast, the 825 T allele was suggested to be related to dyspepsia in reports from Japan and the Netherlands.117–119 In Japanese groups, the following polymorphisms have been reported to be associated with the development of FD or dyspeptic symptoms: IL-17F 7488T, macrophage migration inhibitory factor G-173C,120 catechol-o-methyltransferase gene val158met,121 T779C

of CCK-1 intron 1,122 cyclooxygenase-1 T-1676C,123 p22 phagocyte oxidase component of nicotinamide adenine dinucleotide phosphate oxidase C242T,124 and transient receptor potential vanilloid 1 G315C.125 These data indicate that genetic factors are associated with the development of FD. However, the studies from Asia are limited and are only from Japan. Validation in other countries and in a large-scale study is warranted. Statement 21. Dietary factors and lifestyle may be involved in selleck chemicals llc the pathogenesis of functional dyspepsia. Grade of evidence: low. Level of agreement: a: 94.7%; b: 5.3%; c: 0%; d: 0%; e: 0%; f: 0%. The investigation of lifestyle factors in FD has been limited to a few studies. From Asia, Chen et al.79 and Mahadeva et al.44 reported that tea drinking was negatively associated with FD. Theophylline in tea acts as a competitive antagonist MCE to adenosine receptors, which induce epigastric pain

and chest pain.126,127 However, there is little Asian literature on the types and amounts of tea drunk by dyspeptic patients. More recently, the concept of visceral hypersensitivity to nutrient stimuli, especially hypersensitivity to fat,128,129 has been highlighted as an etiology of FD.130,131 Food ingestion is associated with stimulation of secretion of a range of GI hormones, including cholecystokinin and peptide YY, and suppression of ghrelin.132 It is conceivable that gut peptides play a role in the induction of dyspeptic symptoms in FD patients with nutrient hypersensitivity. In patients with FD, intolerance to specific foods is common and many foods are reported to induce symptoms.133 On the contrary, chili and rice134 and ginger135 are reported to be good for dyspepsia. Feinle-Bisset et al.

For example, mucocutaneous bleeding disorders without a clear aetiology may represent a complex trait with environmental and genetic influences. The genetic component may be determined by the additive effect of many genes with modest-to-moderate effect for each. In general, the genetic analysis of these complex traits has proven to be highly

challenging. Association and linkage studies have been very successful for single gene conditions but their characterization in complex disorders has had limited success. For reasons of the mix of multiple genetic and environmental AZD8055 concentration contributing factors, large families or populations are needed to identify genes of even modest impact. While linkage studies focus on shared chromosomal segments among affected individuals that are closely related, Navitoclax cell line association studies typically compare the frequency of a specific genetic variant in affected individuals to unaffected controls. This can be performed with known functional variants

or with markers that are closely positioned to the causative allele [utilizing a phenomenon known as linkage disequilibrium (LD)] [13]. Association studies are known to provide greater statistical power than linkage studies for complex disorders. However, the traditional case-control approach is limited by the low number of candidate genes available, and also by the lack of replication in subsequent independent studies [14]. The availability of high-density SNPs maps now allows investigators to perform the search of gene variants involved MCE公司 in disease through whole genome association. This particular approach has sparked a large number of GWAS. These kinds of studies are somewhat limited by their substantial cost. However, the fast decrease in cost of SNP genotyping has made them much more attainable in recent years [15–17]. A significant weakness in current genetic investigations of haemostasis and its complications represented by bleeding or

thrombosis is their dependence on a candidate gene approach. A comprehensive genome-wide search is the only way to identify those genes that would not be suspected based on our current understanding of haemostasis. This non-biased approach should focus on the identification of common variants contributing to the variability of the bleeding phenotype. A disease that has been proposed as a model of a complex bleeding disorder is VWD type 1, which is characterized by incomplete penetrance and variable expressivity. The extent of clinical bleeding in patients with VWD type 1 does not always correlate with VWF levels. Patients with mild or moderate deficiencies may show considerable variation in bleeding tendency even within the same family. Conversely, mild bleeding and bruising are common in the general population without an identifiable bleeding disorder and some symptoms may overlap between bleeders and healthy controls [18].

TNF exerts its biological functions by interactions with two members of the TNF receptor (TNFR) superfamily, namely TNFR1 and TNFR2. The cytoplasmic tail of TNFR1 contains a death domain, which is essential for the induction of apoptosis. However, this motif FDA-approved Drug Library is missing in TNFR2 and the function of this latter receptor is poorly understood.1, 2 In the liver, TNF functions as a double-edged sword through TNFR1, being required for normal hepatocyte proliferation during liver regeneration3, 4 and induction of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), which is essential to elicit antiapoptotic defense and in the control of the immune response.

Yet, on the other hand, TNF is the mediator of hepatotoxicity and inflammation in many animal models and has also been implicated as an important pathogenic player in patients with alcoholic liver disease, nonalcoholic steatohepatitis, or viral hepatitis.5, 6 Human and animal studies suggest that hepatocellular injury, followed by inflammation and activation of the innate immune system, leads to early-stage liver fibrosis, ultimately resulting in hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition.7, 8 Although

the contribution of TNF to hepatocellular injury and inflammation has been widely studied,5, Selleckchem Ibrutinib 6, 9, 10 its specific contribution to HSC activation and liver fibrogenesis remains controversial. In this sense, experimental MCE studies performed with knockout mice after carbon tetrachloride (CCl4) administration have shown that the absence of either TNFR111 or TNFR1/R2 double-knockout (TNFR-DKO)12 mice inhibit liver fibrosis accompanied by reduced expression of procollagen-α1(I) messenger RNA (mRNA), without effect on hepatic injury, suggesting a profibrogenic role for TNF. In contrast, a recent study showed that the inhibition of TNF processing via TNF-alpha–converting enzyme attenuated liver injury and inflammation after CCl4 administration, but increased collagen deposition, effects reproduced in the

TNFR-DKO mice.13 Moreover, several reports using cultured HSCs point to an antifibrogenic role of TNF via the inhibition of procollagen-α1(I) gene expression14-17 due, in part, to glutathione depletion.18 Hence, although TNF has been implicated in the progression of many chronic liver diseases leading to fibrosis, the specific involvement of TNF or its receptors, TNFR1 and TNFR2, in HSC activation remains to be established. The morphological and metabolic changes associated with HSC activation, reproduced by culturing isolated HSCs on plastic,19, 20 were studied in HSCs from wild-type, TNFR-DKO, TNFR1, and TNFR2 knockout mice to evaluate the impact of TNF signaling and thus its potential direct contribution to liver fibrosis.

TNF exerts its biological functions by interactions with two members of the TNF receptor (TNFR) superfamily, namely TNFR1 and TNFR2. The cytoplasmic tail of TNFR1 contains a death domain, which is essential for the induction of apoptosis. However, this motif learn more is missing in TNFR2 and the function of this latter receptor is poorly understood.1, 2 In the liver, TNF functions as a double-edged sword through TNFR1, being required for normal hepatocyte proliferation during liver regeneration3, 4 and induction of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), which is essential to elicit antiapoptotic defense and in the control of the immune response.

Yet, on the other hand, TNF is the mediator of hepatotoxicity and inflammation in many animal models and has also been implicated as an important pathogenic player in patients with alcoholic liver disease, nonalcoholic steatohepatitis, or viral hepatitis.5, 6 Human and animal studies suggest that hepatocellular injury, followed by inflammation and activation of the innate immune system, leads to early-stage liver fibrosis, ultimately resulting in hepatic stellate cell (HSC) activation and extracellular matrix (ECM) deposition.7, 8 Although

the contribution of TNF to hepatocellular injury and inflammation has been widely studied,5, Selleckchem RAD001 6, 9, 10 its specific contribution to HSC activation and liver fibrogenesis remains controversial. In this sense, experimental MCE studies performed with knockout mice after carbon tetrachloride (CCl4) administration have shown that the absence of either TNFR111 or TNFR1/R2 double-knockout (TNFR-DKO)12 mice inhibit liver fibrosis accompanied by reduced expression of procollagen-α1(I) messenger RNA (mRNA), without effect on hepatic injury, suggesting a profibrogenic role for TNF. In contrast, a recent study showed that the inhibition of TNF processing via TNF-alpha–converting enzyme attenuated liver injury and inflammation after CCl4 administration, but increased collagen deposition, effects reproduced in the

TNFR-DKO mice.13 Moreover, several reports using cultured HSCs point to an antifibrogenic role of TNF via the inhibition of procollagen-α1(I) gene expression14-17 due, in part, to glutathione depletion.18 Hence, although TNF has been implicated in the progression of many chronic liver diseases leading to fibrosis, the specific involvement of TNF or its receptors, TNFR1 and TNFR2, in HSC activation remains to be established. The morphological and metabolic changes associated with HSC activation, reproduced by culturing isolated HSCs on plastic,19, 20 were studied in HSCs from wild-type, TNFR-DKO, TNFR1, and TNFR2 knockout mice to evaluate the impact of TNF signaling and thus its potential direct contribution to liver fibrosis.

6C). These results are consistent with decreased mRNA levels (Fig. 4A) and decreased occupancy of RNAPII and acetylated H3 levels at

those genes (Fig. 5C-F). Collectively, these studies suggest that a large fraction of the agonist-activated FXR target genes examined is directly repressed. Because FXR was shown to increase its target genes in nearly all previous studies and to repress some target genes indirectly through the induction of SHP,3, 4, 11, 14 our finding that direct gene repression by FXR is common is unexpected. In this study, ChIP-seq analysis of hepatic genomic binding of agonist-activated FXR in healthy and obese mice resulted Selleckchem Sotrastaurin Dasatinib concentration in two major findings. First, of the total hepatic FXR-binding sites, nearly half of the sites were unique to healthy or obese mice, implying altered FXR transcriptional signaling in obesity. Second, further analyses utilizing ChIP and qRT-PCR assays suggested that a large fraction of FXR target genes examined are directly repressed by ligand-activated FXR. Approximately 80% of identified FXR-binding sites are localized in intergenic and intron regions, at a consensus IR1 motif, in healthy and obese mice. These findings are consistent

with recently reported ChIP-seq analysis of FXR binding in healthy

mice.26-28 Thomas et al., for the first time, identified and compared genomic FXR-binding sites in liver and intestine in mice treated with GW4064. Interestingly, only 11% of total FXR-binding sites were shared between liver and intestine, demonstrating tissue-specific FXR target genes.26 Chong et al. identified FXR-binding sites in mouse hepatic chromatin, and showed that binding sites for liver receptor homolog 1 (LRH-1) were enriched near the asymmetric IR1 FXR site and that LRH-1 and FXR can coactivate gene expression.27 Lee et al. also identified functional FXR sites within promoters, introns, 上海皓元医药股份有限公司 or intragenic regions of selected genes involved in xenobiotic metabolism, suggesting a role for FXR in liver protection against toxic substances, such as acetaminophen.28 This current study reveals numerous previously unknown potential FXR target genes unique in healthy and obese mice and categorization of these genes identifies new functions, suggesting that biological pathways potentially regulated by FXR are altered in obesity. We have shown that acetylation of FXR inhibits DNA binding of the FXR/RXRα heterodimer, and that FXR acetylation levels are highly elevated in obese mice.