miRNAs were characterized using a commercially available assay that measures expression of 84 miRNAs, which were subsequently validated

by real-time reverse-transcriptase polymerase chain reaction. In the first phase of the study, the team compared serum miRNA profiles among HCV-infected patients with fibrosis versus healthy volunteers. A total of 44 subjects with chronic HCV infection were studied, including 33 with early-stage fibrosis (F0-F2) and 11 with late-stage fibrosis (F3-F4). Twenty subjects with non-HCV Venetoclax fibrosis and 22 healthy subjects served as controls. In the second phase, plasma miRNA profiles of 10 healthy volunteers were compared to 29 patients with acute HCV infection, 18 who progressed to chronic HCV infection and 11 who spontaneously resolved the infection. Subjects were https://www.selleckchem.com/products/AZD2281(Olaparib).html recruited from St. Louis University and Massachusetts General Hospital. The investigators reported that serum miR-20a and miR-92a levels were significantly higher in HCV+ subjects

with fibrosis, compared to healthy volunteers or non-HCV-associated liver disease. Moreover, the abundance of these two miRNAs was increased in patients with both acute and chronic infection, as compared to healthy volunteers. However, degree of enhancement of miR-20a and miR-92a in HCV infection was independent of viral load. In longitudinal samples, both miR-92a and miR-20a remained elevated and relatively stable during transition from acute to chronic infection, whereas miR-92a decreased as patients spontaneously resolved their acute infection. Receiver operating characteristic analyses suggested that these miRNAs discriminated infected from noninfected

patients, HCV+ patients with or without fibrosis, acute versus noninfected, and chronic versus noninfected subjects. Finally, miR-20a and miR-92a were induced in cultured hepatoma cells after in vitro HCV infection. Although miR-92a and many other miRNAs are implicated in liver disease in animal models and in humans,[1, 10] the article from Shrivastava et al. is the first report describing an association of miR-20a with HCV-associated fibrosis (Fig. 1). Other recent studies have shown that miRNAs associated with inflammation, such as miR-155, a positive Etofibrate regulator of tumor necrosis factor alpha production, is up-regulated in serum and circulating monocytes from patients with HCV infection,[11] that miR-199 and miR-200 families in liver are associated with progression of fibrosis,[12] that hepatic miR-21 correlates with viral load, fibrosis, and levels of serum liver transaminases, possibly through induction of transforming growth factor beta signaling,[6] and that HCV infection is associated with decreased hepatic miR-29, which is associated with induction of extracellular matrix proteins by hepatic stellate cells.

1A). HNF-4α/PGC-1α promoted both the wild-type and ΔA reporter expression levels (Fig. 1C). On the other hand, this HNF-4α/PGC-1α–driven expression was lost by deleting or mutating site B (Fig. 1C). Similar results were obtained in human hepatocarcinoma HepG2 cells (Supporting Information Fig. 1). We next investigated if HNF-4α can bind to site B response element. We prepared nuclear Hydroxychloroquine supplier extracts from cells infected with

a control adenovirus (Adeno-ΔE1E3) or an adenovirus encoding HNF-4α (Adeno-HNF-4α) to perform electrophoresis mobility shift assays (EMSAs). Using a biotin-labeled oligonucleotide based on site B sequence as a probe, we found that Adeno-ΔE1E3 nuclear extract bound to this probe, generating several nonspecific bands that were not competed by a nonlabeled site

B probe (Fig. 1D). In contrast, Adeno-HNF-4α nuclear extract specifically bound to the probe selleck generating a specific band that was competed by a wild-type but not by a mutant site B nonlabeled probe (Fig. 1D). In addition, this specific band was super-shifted by an antibody against HNF-4α (Fig. 1D), indicating that HNF-4α binds to site B probe specifically in vitro. We then used a chromatin immunoprecipitation (ChIP) analysis to confirm that liver HNF-4α binds to site B in vivo. An antibody against HNF-4α immunoprecipitated a chromatin fragment containing site B; whereas, a nonspecific antibody (immunoglobulin G [IgG]) or mock control did not (Fig. 1E). On the other hand, none of the antibodies or the mock control immunoprecipitated a chromatin fragment spanning site A (Fig. 1E). As a positive control, we found that a chromatin fragment spanning the published HNF-4α binding site on G6P was specifically Dichloromethane dehalogenase pulled down by the HNF-4α antibody (Fig. 1E). Collectively, our analysis indicated

that HNF-4α and PGC-1α control the expression of PLA2GXIIB through a bona fide HNF-4α response element located at site B. To further address if modulating HNF-4α activity alters PLA2GXIIB expression, we first used the HNF-4α agonistic modulators propionate and butyrate to enhance HNF-4α activity.2, 10 HeLa cells were transfected with either the wild-type or site B mutant reporter plasmid together with HNF-4α and PGC-1α expression vectors. We found that the HNF-4α/PGC-1α–driven pGL3-mPLA2GXIIB reporter expression was further enhanced by both propionate and butyrate (Fig. 2A); whereas, these treatments had no effect on the site B mutant reporter (Fig. 2A). In addition, we found that the messenger RNA (mRNA) expression level of PLA2GXIIB was induced by propionate and butyrate in HepG2 cells, which express HNF-4α endogenously (Fig. 2B).

The magnitude of TP was similar among the control subjects and subjects with <11% FVIII. In severe subjects with <1% FVIII at the time of blood collection, the TAFIa20 min was inversely and significantly correlated with haemarthrosis (−0.77, P = 0.03) and total bleeds (−0.75, P = 0.03). In all cases, TAFIa20 min was more strongly correlated with bleeding than TAT levels at 20 min. Overall, this study shows that TAFI activation

in whole blood can be quantified and related to the clinical bleeding phenotype. Measuring TAFIa along with thrombin generation can potentially be useful to evaluate the differential bleeding phenotype in haemophilia A. “
“Adults with haemophilia have a higher incidence of chronic kidney disease than general male population. JAK inhibitor We recently showed that children with haemophilia have higher urinary calcium excretion and lower whole body bone mineral density than controls in spite of prophylaxis with the deficient coagulation factor concentrate, serum vitamin D concentrations

comparable to those of healthy children and physically active lifestyle. Persistent hypercalciuria may result in nephrocalcinosis and selleck chemicals llc impact renal function. This study sought to assess persistence of urinary calcium excretion and kidney function in children with haemophilia. We investigated retrospectively urinary calcium excretion in 30 children with haemophilia (mean age 12.5 years) from consecutive Tacrolimus (FK506) urine samples over a 2-year period. Renal evaluation included blood and urine specimen, blood pressure, and renal ultrasound. High number of children with haemophilia had intermittent hypercalciuria. Hypercalciuria was not associated with age, severity of haemophilia or previous hypercalciuria. Kidney function and renal ultrasound were normal with the exception of suspected kidney stone in one patient with haemophilia and transient hypercalciuria. Vitamin D concentrations improved after the families had received information and recommendations concerning vitamin D substitution. Our findings indicate that haemophilia per se predisposes to hypercalciuria which may in turn affect bone mineral content

and kidney function. Whether childhood-onset intermittent hypercalciuria contributes to hypertension and renal complications in adulthood remains to be elucidated in future studies. “
“Summary.  A woman with an inherited bleeding disorder faces two main challenges: managing her symptoms medically and integrating her condition into her daily life. Health professionals have an obligation to support young girls and women affected with these disorders as they negotiate the life-cycle transition of their condition. This support should include helping women to integrate their diagnosis into a new sense of self. The psychological effects of menorrhagia can also be addressed by working with key family members such as a young patient’s mother or a woman’s partner to prevent the experience of body shame.

2). Consistent selleck chemical with previous work on this species (Fewell & Page Jr, 1999), the distribution of task sharing in excavation of observed pairs was significantly lower than that predicted from the extent of intrinsic variation in excavation behavior displayed by queens when founding colonies alone (2011: predicted median = 0.55, observed median = 0.19, P < 0.01; 2012: predicted = 0.44, observed = 0.27, P < 0.05; Supporting Information Fig. S1), with the largest

excess in the most extreme level of excavation skew, where one queen performed little or no excavation while the behavior of the excavation specialist was either slightly but significantly lower (2011: t44 = 2.25, P < 0.05) or not significantly different (2012: t62 = 0.61, P = 0.54) from that of solitary queens (Fig. 2). Relative performance of excavation behavior was significantly predicted by patterns of queen–queen aggression during the first 15 min of pair formation

(t50 = 2.02, P < 0.05; Fig. 1c), but not by relative size differences (t50 = −0.24, P = 0.81; Fig. 1b). Both paired queens survived to brood collection in 6 of 28 colonies in 2011 and in 14 of 35 colonies in 2012. In contrast to excavation, Pembrolizumab order total productivity in colonies with two surviving queens was significantly higher than productivity in single nests (main effect of queen number, F1,60 = 23.51, P < 0.001), with the two nest types not differing significantly in average per capita productivity (Student's t-test, t57 = 1.38, P = 0.17; Fig. 3). As with excavation, however, the allocation of offspring in paired nests was significantly more skewed toward a single queen than that predicted by the

distribution of productivity values from single queens (predicted median = 0.60, observed median = 0.40, P < 0.01; Supporting Information Fig. S2). This was caused by both a significant increase in reproduction by HF queens (t38 = 2.05, P < 0.05) and by a reduction in reproduction by the LF queen (t46 = 5.39, P < 0.001) relative to single queens (Fig. 3). Reproductive role was not significantly associated with relative size (t13 = 0.52, P = 0.61; Fig. 4a), relative social dominance (t13 = 0.39, P = 0.71; Fig. 4b) or excavation role (t13 PDK4 = 0.49, P = 0.63; Fig. 4c). Social life involves a complex interplay between individual behavior and patterns expressed at the level of the group as a whole, with the potential for complex group-level patterns and collective behavior from relatively simple individual decision rules (Camazine et al., 2001). Critically, higher level patterns emerge whenever individuals form interactive groups, which may or may not be adaptive but in many cases mimic the properties of socially adapted taxa (Parrish et al., 2002). Our experimental results support the notion that self-organization can produce reproductive division of labor, as predicted by an emergent property model.

Probiotic bacteria produce immune regulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti-carcinogenic effects. This study aimed to learn more investigate the cellular and molecular mechanisms underlying the efficacy of Yakult probiotic bacteria in mouse models of colitis-associated colorectal cancer. Methods: The immune modulatory

mechanisms of Yakult probiotic bacteria were investigated in mouse models of inflammation-driven colorectal cancer. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Results: Mice treated with Yakult recovered faster from the acute inflammatory phase of disease and had lower disease severity in the chronic, tumor-bearing phase of disease. Adenoma and adenocarcinoma formation was also diminished by treatment. Yakult increased the mRNA expression of TNF-α, angiostatin and PPAR γ. Moreover, Yakult -treated mice had increased IL-17 expression in MLN CD4+

T cells and accumulation of Treg LPL and memory CD4+ T cells. Conclusion: Yakult suppressed colon carcinogenesis, and Yakult could show greater anti-carcinogenic and anti-inflammatory activities. Mechanistically, GW-572016 Yakult targeted regulatory mucosal CD4+ T cell responses in the colonic mucosa. Key Word(s): 1. Yakult; 2. mechanisms; 3. Prevention; 4. colorectal cancer; Presenting Author: MAJID KARANDISH Additional Authors: SABA AZADI, NAFISEH SHOKRI MASHHADI Corresponding Author:

MAJID KARANDISH Affiliations: Nutrition and Metabolic Diseases Reserach Center; Ahvaz Jundishapur University of Medical Sciences Objective: Water is an essential nutrient, which plays an important role in prevention of body from dehydration and metabolic oxidation. Very few studies have examined the total fluid intake in different countries, including Iran. The aim of this study was to investigate the total daily water consumption among female university students of nutrition department in Ahvaz, Iran. Methods: Total beverages intake was estimated in female university students of nutrition department in Jundishapur University of Medical Sciences of Ahwaz, Iran. Megestrol Acetate Sixty-nine participants (20–23 years old) attending this department were invited to participate in this study. They completed a three-day food record with an interview. Results: Daily fluids consumption is reported here. Forty-nine of participants completed all aspects of the study (71% of those whom were eligible). The mean total fluids intake (based on foods and beverages) was 1420 ml/d (± 500), and mean total water intake was 695 ml per day (± 300). Conclusion: Water was consumed less than other drinks and fluids, including fruits juice, milk, dough, soft drinks, sugar-sweetened beverages, coffee, and tea.

[12] Cell migration was assessed using cell-culture inserts (BD Biosciences, Bedford, MA), according to the manufacterer’s guidelines. EMD 1214063 solubility dmso Details are provided in the Supporting Materials. The sphere formation assay was performed as previously described[13] (and in the Supporting Materials). Flow cytomety analysis was performed as previously described[13] and detected using a FACSCanto

II flow cytometer (BD Biosciences). Antibodies (Abs) and the procedure are described in the Supporting Materials. The 3′-UTR (untranslated region) sequence of PTEN and SMAD7 are predicted to interact with miR-216a, and miR-217 or a mutated sequence within the predicted target sites was synthesized and inserted into the XbaI and FseI sites of the pGL3 control luciferase reporter vector (Promega, Madison, WI) (Supporting Fig. 3). The luciferase reporter assay was performed as previously described[11, 13] (and in the Supporting Materials). All experiments on mice were approved by the SingHealth Institutional Animal Care and Use Committee. Details of animal studies are provided in the Supporting Materials. Experimental data are presented as the mean ± standard deviation (SD). All statistical analyses were performed using analysis of variance (ANOVA) or a two-tailed Student t test with either GraphPad

Prism 5 (GraphPad Software, Inc., La Jolla, CA) or Partek Genomics Suite software (Partek Incorporated, St. Louis, MO). Survival curves were

calculated using Kaplan-Meier’s method. Differences Crizotinib mw were considered statistically significant when P values were less than 0.05. Because there have only been a few reports on the expression of miRNAs and their relation to early recurrent disease in patients with HCC, we conducted Cyclin-dependent kinase 3 comprehensive miRNA profiling of liver biopsies from HCC patients with early and nonrecurrent diseases to identify miRNAs that are relevant to early recurrent disease. Early recurrence was defined as a recurrence within 2 years after a curative resection. miRNA expression profiles of 30 cases of liver biopsies, including 10 samples from HCC patients who had early recurrent disease over the 24-month observation period and 10 from patients who did not have early recurrent disease, were compared to 10 histologically normal tissue samples using the GeneChip miRNA 2.0 Array (Affymetrix, Inc., Santa Clara, CA). A panel of miRNAs with significant differential expression between early and nonrecurrent HCC and histologically normal liver tissue was derived through a series of ANOVA contrasts, and these miRNAs were selected for further validation and functional characterization. Among these miRNAs, expression of the miR-216a/217 cluster was significantly up-regulated in biopsies from HCC patients associated with early recurrent disease. Expression of miR-216a and miR-217 was >20- and >16-fold, respectively, when compared between HCC and normal liver tissue.

[2] The patients with CoCC, HCC or classical CHC were more likely to have suffered from hepatitis virus B or C infection and liver cirrhosis than the patients with CCC (P < 0.001). The tissue samples were fixed in a 10% formalin solution and embedded in paraffin for histological diagnosis and immunohistochemistry. We used the new WHO classification for the histological diagnosis of CoCC, CCC, HCC and classical CHC.[3] The diagnosis of CCC and the CCC components within classical CHC was

confirmed with Alcian blue histochemical staining for mucin and immunostaining for cytokeratin (CK)7 and epithelial membrane antigen (EMA); HCC and the HCC components of classical CHC were diagnosed using immunostaining for α-fetoprotein (AFP), hepatocyte paraffin 1 and BMN 673 solubility dmso arginase in addition to histological findings. This study was approved by the Research Ethics Review Board of Teikyo University KU57788 School of Medicine (no. 08–159). Formalin-fixed paraffin-embedded tissue sections, cut at a thickness of 3 μm, were deparaffinized with xylene and rehydrated with

graded ethanol. Immunohistochemistry was performed using monoclonal and polyclonal antibodies with antigen-retrieval methods, as listed in Table S1, and performed using Dako Autostainer Link 48 (Dako, Glostrup, Denmark). Endogenous peroxidase was quenched with 3% H2O2 in distilled water for 5 min. The slides were incubated with primary antibodies for 30 min at room temperature, and the sections were then stained by a detection method using EnVision FLEX (Dako) according to

the manufacturer’s protocol and counterstained with hematoxylin. Immunostaining for the integrins β6, β4 and α3, fibronectin and laminin was defined as positive when more than 10% of positively stained cells or areas were observed. Moreover, the intensity of integrin β6, β4 and α3 staining was semiquantitatively scored as 0 (negative), 1 (weak), 2 (moderate) see more or 3 (strong). The percentage of cells staining positively for integrins β6, β4 and α3 was also semiquantitatively scored into five categories: 0 (<10%), 1 (11–25%), 2 (26–50%), 3 (51–75%) or 4 (76–100%). To perform the statistical analysis, the level of positive staining was evaluated by a final score, which was calculated by multiplying the scores of staining intensity by the scores for the percentage of positive cells. Based on the final score for integrin β6, β4 and α3 staining, the cases were grouped as negative for a score of 0, low for 1–2 and high for 3–12. The predominant pattern of positive staining for the integrins and ECM proteins in the hepatic tumors was classified as a cytoplasmic pattern, cell membrane pattern, basal lamina pattern or stromal pattern.

After incubation, cells were washed with permeabilization solution as indicated by the manufacturer, fixed in paraformaldehyde, BMN 673 in vivo and analyzed by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) were separated from blood of healthy volunteers by centrifugation in Ficoll gradient as described.16 Primary hepatocytes and LMNCs were cultured in Dulbecco’s modified Eagle’s

medium containing 10% fetal bovine serum and 1% insulin, transferrin, selenium (ITS) solution. Primary hepatocytes were seeded in 6-well collagen-coated plates, LMNCs (106/insert) were plated in cell-culture inserts with pore diameter 0.4 μm (Becton Dickinson Labware, Bedford, MA). Before starting stimulation experiments, hepatocytes were rested for 4 hours. Subsequently, culture media was replaced and stimulation was performed as indicated in the figure legends. LPS (Sigma, St. Louis, MO) was used at 100

ng/mL. IFN-β, IL-10, and TNF-α were measured in supernatants using ELISA. RAW264.7 macrophages were stimulated with LPS, recombinant mouse IFN-α2a (eBioscience, San Diego, CA), recombinant mouse IL-10 (PeproTech, Rocky Hill, NJ), or with antimouse IL-10 receptor antibody (Biolegend, San Diego, CA). Human PBMCs were stimulated with LPS, recombinant human IFN-α (PBL Interferon Source), recombinant IL-10 (eBioscience), or IL-10 receptor antibody (R&D Systems). Statistical significance was determined using the t-test or the nonparametric selleck products Kruskal-Wallis test using the GraphPad Prism 5.01 (La Exoribonuclease Jolla, CA). Data are shown as mean ± standard error of the mean (SEM) and were considered

statistically significant at P< 0.05. TLR4 recognizes LPS and activates two signaling pathways by utilizing the adaptor molecules MyD88 or TRIF, respectively. We showed that MyD88 is dispensable in ALD.13 In addition to induction of inflammatory cytokines by way of NF-κB, MyD88-independent activation of TLR4 triggers production of Type I IFNs, which is largely dependent on activation of intracellular pathways involving interferon regulatory factor-3 (IRF3).12 To define the importance of the MyD88-independent, IRF3-dependent signaling cascade and Type I IFNs in alcohol-induced liver injury, we fed ethanol or isocaloric control (pair feeding) diet to WT and IRF3-KO mice. Histopathological analysis revealed that chronic alcohol feeding induced micro- and macrovesicular steatosis and inflammatory cell recruitment in ethanol-fed WT mice, suggestive of ALD (Fig. 1A). In contrast, none of the histopathological features of ALD were observed in IRF3-KO mice (Fig. 1A). Consistent with the histopathology, serum ALT levels were significantly higher in alcohol-fed WT mice, but not in the IRF3-KO mice, compared to the pair-fed controls (Fig. 1B).

To test this hypothesis, we introduced into hepatocytes a specific fluorescent calcium probe that targets ER: D1ER (Fig. 3A). This new-generation calcium probe contains a calcium-binding domain and uses the FRET principle to quantify the level of calcium at the specific subcellular site where it is located.17 The

FRET signal is in proportion to the amount of calcium binding to this probe. Using this probe, we found that WT hepatocytes had a higher level of calcium in the ER than Bid-deficient hepatocytes (Fig. 3B,C). TG is an inhibitor of sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA), which is required for the reuptake of calcium leaking from the ER. Thus, TG causes a continuous decrease in the ER calcium level. We found no significant differences between WT and Bid-deficient hepatocytes buy Smoothened Agonist in terms of the kinetics of the TG-induced reduction, but WT cells consistently possessed a higher level of ER calcium

than Bid-deficient hepatocytes until virtually all ER calcium was depleted (Fig. 3B,C). These findings suggested KU-57788 that Bid was important for the maintenance of the ER calcium storage level. In the absence of Bid, this lower level of ER calcium storage would lead to a lower level of cytoplasmic calcium after release from the ER and subsequently a lower level of store-operated calcium entry (SOCE). This notion was supported by the measurement of the cytosol calcium level with another calcium probe, YC2.3, which is located in the cytoplasm17 (Fig. 3D). After TG treatment, the accumulation of calcium in the cytoplasm of Bid-deficient hepatocytes was much less than that in the WT hepatocytes (Fig. 3E). We also found that the ability of Bid to regulate ER calcium homeostasis was not limited to hepatocytes. Bid-deficient T lymphocytes12 and murine embryonic fibroblast cells (MEFs; Supporting Information Fig. 1A) also displayed a reduced proliferative response to mitogen stimulation. The introduction of YC2.3

into the WT MEFs indicated a calcium increase in the cytosol followed by TG treatment, which was significantly blunted in Bid-deficient MEFs (Supporting C-X-C chemokine receptor type 7 (CXCR-7) Information Fig. 1B). Using a different approach to calcium measurement with the fura-2-acetoxymethyl ester dye, we found that the basal level of cytosol calcium, the inositol-1,4,5-trisphosphate (InsP3)–sensitive calcium store, and the total intracellular calcium store were all reduced in Bid-deficient MEFs (Supporting Information Fig. 1C-F). Consistently, SOCE, as measured by the Mn2+ quenching method, was also reduced in Bid-deficient MEFs (Supporting Information Fig. 1G,H). Together, these findings from different approaches indicated that Bid could regulate ER calcium homeostasis. To determine that the calcium level was indeed responsible for the effects of Bid on hepatocyte proliferation, we included a calcium ionophore, ionomycin, in the culture medium together with the serum.

Genetic ablation of Them1 in mice decreases hepatic FFA concentrations and improves glucose tolerance in high fat fed mice, putatively

by reducing endoplasmic reticulum Trametinib stress. However, because Them1-deficient mice also exhibit increased energy expenditure and resistance to diet-induced obesity, the contribution of Them1 expression in liver to NAFLD remains unclear. Aim: This study was designed to assess the specific contribution of hepatic Them1 expression to glucose metabolism in high fat fed mice. Methods: We designed conditional Them1 transgenic (c-Them1Tg) mice with Cre recombinase-dependent Them1 overexpression. Liver-specific Them1 transgenic (L-Them1Tg) mice were generated by infection with Cre recombinant adenovirus in c-Them1Tg mice. Control mice were infected with GFP recombinant adenovirus. Hepatic Them1 expression was assessed by immunoblot analysis. Mice were fed high fat (60% of kcal) diet for 2 w. Body composition was determined by magnetic resonance

spectroscopy. For tolerance tests (n=5 mice/group) to insulin (ITT), pyruvate (PTT) or glucose (GTT), PF-02341066 cell line plasma glucose concentrations were determined in fasting mice and then periodically up to 90 min after i.p. injection of insulin (1 U/kg bw), pyruvate (2 mg/g bw) or glucose (1 mg/g bw) respectively. Mice were maintained on the high fat diet and allowed to recover for 7 days between each test. Results: L-Them1Tg mice exhibited a 3.4-fold increase

in the hepatic expression of Them1 compared with c-Them1Tg control. Total body weights, fat and lean masses of L-Them1Tg were similar to c-Them1Tg control mice, as were fasting plasma glucose concentrations. Indicative of decreased clearance rate of exogenous glucose, plasma glucose concentrations in L-Them1Tg mice were higher at each time point during find more the GTT and the area under the curve was increased by 43% (c-Them1Tg, 16,532±1377, L-Them1Tg, 23,610±883; P=0.0025). By contrast, there were no differences in the ITT, which reflects whole body insulin sensitivity, or in the PTT, which estimates hepatic glucose production. Conclusion: Without altering body composition, liver-specific Them1 overexpression promotes glucose intolerance in high fat fed mice. These findings suggest a primary contribution of hepatic Them1 to the pathogenesis of NAFLD that is distinct from its function in suppressing energy expenditure. Disclosures: David E. Cohen – Advisory Committees or Review Panels: Merck, Genzyme; Consulting: Novartis, Aegerion, Dignity Sciences, Intercept; Speaking and Teaching: Merck The following people have nothing to disclose: Cafer Ozdemir Saturated fatty acids, such as palmitic acid (PA), play a key role in lipotoxicity and the pathogenesis of NASH. Sustained JNK activation is a key mechanism of lipotoxicity. Little is known about how JNK mediates the lethal lipotoxic effect of PA in hepatocytes.