Aberrant crypt foci (ACF), which were first discovered in mice treated

with azoxymethane (AOM)[13] have been clearly shown to be precursor lesions of CRC and are now established as a biomarker of the risk of CRC in AOM-treated mice and rats.[14] In humans, ACF are considered as a possible biomarker of the risk of CRC (Fig. 2).[15] Previous studies have demonstrated that individuals with CRC have a larger number of ACF than those without CRC. Recently, an association between obesity and the risk of CRC was suggested.[16, 17] We demonstrated a significant correlation between the number of dysplastic ACF and the visceral fat area (VFA), as measured on abdominal computed tomography (CT) images, and also a significant inverse correlation MK-2206 in vivo between the former and the plasma adiponectin levels (Table 1).[3, GS-1101 molecular weight 18] Several reports have suggested the existence of relationships between the risk of CRC and exercise, energy use, glycemic index, food choices, and dietary constituents.[19-21] As these factors also often influence one another, it is difficult to evaluate the relationship between any one of these factors alone and the risk of CRC; however, obesity is known to be related to many of these factors. We demonstrated the existence of a relationship between the number of ACF and the serum levels of peroxisome proliferator-activated receptor (PPAR)-γ or insulin-like

growth factor-1 in humans.[22, 23] To clarify the role of obesity and reduced plasma adiponectin levels in colorectal carcinogenesis, further studies were conducted using mouse models. We demonstrated that obesity is an important risk factor for colorectal carcinogenesis in humans using the number of ACF as a surrogate marker of CRC.[18] Epidemiological studies have revealed that obesity, especially visceral obesity, is associated with an elevated risk of colon adenoma and CRC; in addition, the results of animal

experiments also suggest the existence of a link between obesity and CRC.[24, 25] Obesity is strongly associated with adipose tissue dysfunction and altered serum levels of adipokines, which might underlie the elevated risk of CRC associated with it.[26] Adiponectin, also known as ACRP30 or AdipoQ, is a 30-kDa adipokine selleck chemicals composed of 247 amino acids.[27, 28] Several clinical studies in humans have reported the existence of a relationship between the plasma levels of adiponectin and the risk of CRC.[17, 29] However, there had been no animal model studies on the relationship between the serum adiponectin levels and the risk of CRC until our study carried out using adiponectin-deficient mice was published.[30] Therefore, the mechanism underlying the promotion of colorectal carcinogenesis by adiponectin deficiency remains unclear. We investigated the effect of adiponectin in suppressing the development of CRC under the normal and high-fat diet conditions in an AOM-induced CRC model.

Among them, 48 HCC liver tissues (24 males and 24 females) were used for screening the expression patterns of 29 miRNAs, including the paired tumorous and the adjacent nontumorous liver tissues from each patient. The nontumorous liver tissues from 13 focal nodular hyperplasia (FNH) patients (seven males and six females) were included as normal liver control in the current study. An additional 10 paired HBV-related male HCC samples were included for examining the relationship between androgen receptor (AR), tumor suppressor in lung cancer-1 gene (TSLC1),

and miR-216a clinically. And 22 dysplastic nodules were collected from eight HBV-related males, who received surgical resection for clinical diagnosis of HCC but postoperative pathology found dysplasia only for analyzing the expression of miR-216a. The resected surgical specimens were quickly KPT-330 chemical structure kept in liquid nitrogen until the protein and RNA extraction. The Institutional Review Board of National Taiwan University Hospital approved the

use of these archived tissues. The total RNA isolated from HepG2 cells was used for 5′ RACE to determine the transcriptional starting site (TSS) of pri-miR-216a using the SMARTer RACE complementary DNA (cDNA) amplification kit (ClonTech, Mountain View, CA) by following the manufacturer’s LY294002 mouse protocol. The pri-miR-216a-specific primers used for polymerase chain reaction (PCR) reaction were 216SP-R (for first PCR): 5′-CACAGTTGCCAGCTGAGATTAAGC-3′, and 216SP-NR (for nested PCR): 5′-AACTCACAGCCATCCGTGTTAGAC-3′. The PCR product was cloned into the yT&A vector (Yeastern Biotech, Taipei, Taiwan) by TA cloning and processed for sequencing analysis to determine the TSS of pri-miR-216a. We constructed five reporter plasmids, pGL3-216PA to pGL3-216PE, with the luciferase expression driven by different lengths of genomic regions upstream of selleck screening library TSS of pri-miR-216a. The

genomic fragments were amplified by primer sets as follows, using the genomic DNA from HepG2 cells as template. The same reverse primer was used for all the PCR reactions, 5′-AGCCTCGAGATGGCTAAGTGAGACTGAGC-3′ (with XhoI site underlined), and different forward primers were used for amplifying each construct as follows: 216PA, 5′-AGCGGTACCCACAGGGATGTAGAATGCAC-3′; 216PB, 5′-AGCGGTACCGTCATTCATGTTGCTCTGAG-3′; 216PC, 5′-AGCGGTACCCTTAGGAGTCCATATGAGGC-3′; 216PD, 5′-AGCGGTACCACAGTGCCAACACTTGGAAG-3′; 216PE, 5′-AGCGGTACCGGTCTAGTATGAAGTGAAGC-3′ (with KpnI site underlined). The amplified DNA fragments were cloned into the KpnI/XhoI sites of the pGL3-basic vector (Promega, Madison, WI). Two mutant constructs for pGL3-216PD, mut-1 and mut-2, were constructed by introducing the specific mutations using the QuikChange XL Site-Directed Mutagenesis Kit (Stratagene, Cedar Creek, TX).

, 2006). Finally, the formant frequency spacing (formant dispersion, Df) and the corresponding vocal tract length (VTL) were estimated according to Reby & McComb (2003b). We first investigated which acoustic parameters differed between the species and populations using linear mixed effects models with maximum likelihood (Crawley, 2007). Each comparison (species and population) was

analysed in separate models and P-values were used to evaluate significance. Individuals were fitted as random factors to control for repeated sampling. We carried out further 2 × 2 comparisons between European fallow deer populations using Bonferroni–Holm correction to avoid potential type I errors (Rice, 1989). We conducted a nested permuted discriminant function analysis (pDFA) to verify if groans could be correctly CHIR-99021 price classified to groups (species, population) by controlling for recordings from multiple

individuals (Mundry & Sommer, 2007). Before conducting the pDFA, we performed a principal component analysis (PCA) to eliminate redundancy among the parameters (12 in total) because of high intercorrelation (Jolliffe, 2005). PCs with eigenvalues greater than 1 (Kaiser’s criterion) were then used as variables in the pDFA. It was not possible to measure all acoustic parameters in each call and therefore, missing values were replaced by the average of each variable for a given individual for the PCA and pDFA (15.28% data replaced). In order to prevent this procedure from overly affecting the results, we reduced the number of calls for the PCA Selleckchem LDE225 and pDFA, by mainly keeping calls in which all parameters could be measured (species: N = 229; populations: N = 173). Normal distributions of the data were determined by visually inspecting Q–Q plots and scatterplots of the residuals of the dependent variables. Some variables were then log-transformed to reach normal distributions (see Table 2). All statistical tests were

carried out using R version 2.14.0 (R Development Core Team, 2012). All tests were check details two-tailed, except the pDFA, which was one-tailed (because of the predicted direction of results; Mundry & Sommer, 2007), and significance levels were set at 0.05. Persian fallow buck common groans are relatively noisy calls, slightly less than 1-s long, with visible pulses and low F0. Six formants were present below 2600 Hz (Fig. 2, Table 1, Supporting Information S1). The first two formants remained flat across the groan whereas the upper formants (3–6) decreased after the start (Fig. 2). In a small proportion of cases (11%, 14/128), formant frequencies increased towards the end of the call. On rare occasions (n = 13), bucks (4/6) produced harsh groans. Harsh groans were noisier, and the pulses, formants and the formant decrease were less defined (Fig. 3). They were not used for detailed analyses because of their rarity. The highest call rate achieved by a Persian buck was 34 per minute (mean = 8.80 ± 0.

3C). The importance of these genes to liver fibrosis and inflammation is not yet fully understood. However, recent studies have demonstrated that Igfbp7, which is highly expressed in Mdr2:CCR1 DKO mice, functions as a potential tumor suppressor

for HCC.[26] This may explain why, in the presence of inflammation and fibrosis, growth of tumors in Mdr2:CCR1 DKO mice is attenuated. Here, we showed that liver fibrosis in Mdr2-KO mice is dependent on CCR5 expression. In humans, fibrosis is believed to be a prerequisite for HCC. To test the effect of CCR5 and CCR1 depletion EGFR inhibitors cancer on tumor development, we performed monthly MRI scans of Mdr2-KO, Mdr2:CCR1 DKO, and Mdr2:CCR5 DKO mice starting from the age of 9 months. At the age of 9 months, all strains exhibited hepatomegaly, compared to age-matched WT controls. At the age of 16 months, MRI scanning revealed that 75% of Mdr2 KO mice had detectible tumors in the liver, as opposed to only 33% of Mdr2:CCR5 DKO mice (Fig. 4A). Interestingly, tumors in Mdr2:CCR1

DKO mice were already detectible at 13 months of age, and by the age of 16 months 88% had detectable tumors, suggesting that tumorigenesis in these mice is not affected. At the age of 16 months, Mdr2-KO and Mdr2:CCR1 DKO mice revealed sever inflammation associate with fibrosis and increased body/liver index (Fig. 4B). In accord with MRI scanning, macroscopical analysis of harvested livers from 16-month-old mice revealed that 90% of Mdr2-KO and 95% of Mdr2:CCR1 DKO mice had notable scattered tumors. Knocking out CCR5 resulted in a 60% reduction in tumor development selleck compound (Fig. 4C). Furthermore, Mdr2:CCR5 DKO mice that did develop tumors had significantly fewer and smaller tumors, compared to Mdr2 KO mice, resulting in a 20-fold decrease in tumor volume (Fig.

4C). Furthermore, hematoxylin and eosin (H&E) staining of livers from 16-month-old mice revealed that in Mdr2:CCR5 DKO mice that had no macroscopically detected tumors; there was only a mild inflammatory process with a tumor-clear profile and no dysplastic nodules (Fig. 4D). Remarkably, however, Mdr2:CCR1 DKO mice, which began developing tumors earlier than Mdr2-KO mice, learn more had smaller tumors, with a 5-fold decrease in tumor volume, compared to Mdr2-KO mice (Fig. 4E). This may indicate that whereas CCR1 is not crucial in the initiation of inflammatory damage, it may be critical in tumor progression, possibly by controlling the recruitment of the immune cells that support tumor growth. Here we show that the chemokine receptor, CCR5, is at the heart of the inflammatory response that induces tumorigenesis. Macrophages that seem to be the main provokers of the ongoing inflammation in Mdr2-KO mice are completely dependent on CCR5 for their recruitment into the liver. The involvement of macrophages in tumor development and progression is undisputed.

3C). The importance of these genes to liver fibrosis and inflammation is not yet fully understood. However, recent studies have demonstrated that Igfbp7, which is highly expressed in Mdr2:CCR1 DKO mice, functions as a potential tumor suppressor

for HCC.[26] This may explain why, in the presence of inflammation and fibrosis, growth of tumors in Mdr2:CCR1 DKO mice is attenuated. Here, we showed that liver fibrosis in Mdr2-KO mice is dependent on CCR5 expression. In humans, fibrosis is believed to be a prerequisite for HCC. To test the effect of CCR5 and CCR1 depletion CHIR-99021 price on tumor development, we performed monthly MRI scans of Mdr2-KO, Mdr2:CCR1 DKO, and Mdr2:CCR5 DKO mice starting from the age of 9 months. At the age of 9 months, all strains exhibited hepatomegaly, compared to age-matched WT controls. At the age of 16 months, MRI scanning revealed that 75% of Mdr2 KO mice had detectible tumors in the liver, as opposed to only 33% of Mdr2:CCR5 DKO mice (Fig. 4A). Interestingly, tumors in Mdr2:CCR1

DKO mice were already detectible at 13 months of age, and by the age of 16 months 88% had detectable tumors, suggesting that tumorigenesis in these mice is not affected. At the age of 16 months, Mdr2-KO and Mdr2:CCR1 DKO mice revealed sever inflammation associate with fibrosis and increased body/liver index (Fig. 4B). In accord with MRI scanning, macroscopical analysis of harvested livers from 16-month-old mice revealed that 90% of Mdr2-KO and 95% of Mdr2:CCR1 DKO mice had notable scattered tumors. Knocking out CCR5 resulted in a 60% reduction in tumor development selleckchem (Fig. 4C). Furthermore, Mdr2:CCR5 DKO mice that did develop tumors had significantly fewer and smaller tumors, compared to Mdr2 KO mice, resulting in a 20-fold decrease in tumor volume (Fig.

4C). Furthermore, hematoxylin and eosin (H&E) staining of livers from 16-month-old mice revealed that in Mdr2:CCR5 DKO mice that had no macroscopically detected tumors; there was only a mild inflammatory process with a tumor-clear profile and no dysplastic nodules (Fig. 4D). Remarkably, however, Mdr2:CCR1 DKO mice, which began developing tumors earlier than Mdr2-KO mice, find more had smaller tumors, with a 5-fold decrease in tumor volume, compared to Mdr2-KO mice (Fig. 4E). This may indicate that whereas CCR1 is not crucial in the initiation of inflammatory damage, it may be critical in tumor progression, possibly by controlling the recruitment of the immune cells that support tumor growth. Here we show that the chemokine receptor, CCR5, is at the heart of the inflammatory response that induces tumorigenesis. Macrophages that seem to be the main provokers of the ongoing inflammation in Mdr2-KO mice are completely dependent on CCR5 for their recruitment into the liver. The involvement of macrophages in tumor development and progression is undisputed.

These data suggest a contribution Pritelivir ic50 of the MK2/EBP50 pathway in the resistance of liver tumor cells to oxidative stress. Disclosures: The following people have nothing to disclose: Thanh Huong Nguyen Ho-Bouldoires, Audrey Claperon, Martine Mergey, Dominique Wendum, Olivier Scatton,

Chantal Housset, Laura Fouassier Background: The oncofetal protein IMP2–2/p62 has been described to be overexpressed only in a few types of cancer. Gallbladder cancer is a rare but highly malignant, aggressive cancer entity with poor prognosis. Aim of this study was to investigate the implication of p62 on human gallbladder cancer. Methods: Tissue microarrays (TMAs) of 457 gallbladder cancer patients were analysed by immunohistochemistry. Eight different bile duct cancer cell lines were used to develop mouse xenografts. p62 was knocked down by siRNA in different bile duct cancer cell lines. Cell viability was measured by MTT assay. mRNA expression was investigated using real-time RT-PCR, protein expression was determined by Western Blot analysis. Results: Investigation of TMAs stained for p62

revealed overexpression in 66.6% of the tumor samples. Among the positive samples 8.6% highly expressed p62 whereas 91.4% showed mild to moderate expression of p62. Kaplan-Meier curves demonstrated a poor survival linked to high p62 expression (p=0.041; Figure 1). Cell lines, which caused the fastest increase in tumor this website volumes in a xenograft model, highly expressed p62. Upon knockdown of p62 in different bile duct cancer cell lines in vitro, the cytotoxic effect of the chemothera-peutics was increased suggesting a protective role of p62 in cell survival of gallbladder cancer cells.

Conclusion: p62 is overexpressed in gallbladder cancer and is directly associated with poor survival. p62 might therefore display a new bio-marker or therapeutic target for the treatment of gallbladder cancer. Figure 1. Kaplan-Meier survival analysis of gallbladder cancer patients with different expression levels of IMP2–2/p62. Disclosures: check details The following people have nothing to disclose: Sonja M. Kessler, Eva Lederer, Robert Reihs, Alexandra K. Kiemer, Johannes Haybäck (Objective) Generation of hepatocellular carcinoma (HCC) is related with the progression of liver fibrosis. Maid (maternal inhibitor of differentiation) gene, which is HLH transcriptional regulator, binds to Cyclin D1, Rad51, E12, Jab1 and oligo1 and regulates cell cycle and differentiation. From the aspect of TGF-beta signaling and the structure, Maid was stress response regulator and regulated cell inhibition and ECM. In human hepatocarcinogenesis process, we found that HHM (Human homologue of Maid) is specific marker of dysplastic nodule and well-differentiated HCC. Previously we showed that Borte-zomib, a proteasome inhibitor, improved liver fibrosis and generation of HCC. To clarify the mechanism of Maid, we analyzed liver fibrosis and hepatocarcinogenesis in persistent injured Maid KO livers.

“
“Afibrinogenaemia is an autosomal recessive disease with an estimated prevalence of approximately one in a million. The most common symptoms of afibrinogenaemia are umbilical cord bleeding, bleeding into skin, mouth, muscles, gastrointestinal and genitourinary tracts and the central nervous system. Other recognized complications include; haemarthroses, spontaneous splenic rupture, epistaxis, menorrhagia, recurrent abortion and venous and arterial thromboembolism. Bone cysts have also been described

as a rare complication of afibrinogenaemia. The aim of this study was to conduct a systematic literature review, summarize the reported cases and to report two new Metabolism inhibitor cases. Three electronic databases were searched for relevant publications: PubMed, Medline and EMBASE. The following search criteria were used: ‘(bone cysts OR intraosseous haematoma OR intraosseous haemorrhage) AND (afibrinogenaemia OR fibrinogen deficiency)’. The reference lists of the selected papers were searched for more relevant literature. In total, eight patients had bone cysts as complication of afibrinogenaemia and six of http://www.selleckchem.com/products/PD-0332991.html them

suffered from pain in their extremities. Bone cysts were primarily located in the vicinity of the cortex or trabeculae in the diaphysis of the long bones, especially in the femora, tibiae and humeri. Some were regressive, probably due to reactive

bone remodelling. A number of cysts were filled with serosanguinous fluid. It might be useful to check for bone cysts when patients with congenital afibrinogenaemia complain of ‘rheumatic’ pains in their extremities. Whole body magnetic resonance imaging is the diagnostic imaging technique of choice. Recurrent episodes of pain, but not radiological deterioration, appear to benefit from prophylactic check details therapy with fibrinogen concentrate. “
“Summary.  The efficacy and safety of Optivate® was assessed in 23 surgical operations, orthopaedic (12) including 5 revision arthroplasties, ophthalmic (1), ENT (1), dental (6), liver biopsy (2), and removal of portacath (1) on 15 teenagers and adults with severe haemophilia A. The preoperative dose was calculated to raise the FVIII concentration to 100 IU dL−1. Subsequent doses were targeted to maintain at least 50 IU dL−1. There were 11 major and 12 minor operations categorized as receiving intensive replacement therapy for ≥5 days or <5 days respectively. The median preoperative dose was 50.4 (range 18.2–88.2) IU kg−1. The median incremental recovery based on this first dose in 10 procedures (5 patients) was 2.9 (range 2.4–3.4 IU dL−1) per IU kg−1. The daily doses decreased during the first 4 days of the study. The patients in this study received 173 infusions in total.

Observations from several studies extend the functional repertoire of CagA and the cag type IV secretion system BMN 673 in vivo in particular, providing further mechanistic understanding of how these important determinants engage and activate host signalling pathways important in

the development of disease. Helicobacter pylori has evolved numerous strategies to enable its survival and persistence within the gastric mucosa including diverse mechanisms to evade host immune surveillance. Further investigation of one such mechanism, protein glycosylation, has revealed three different glycosylation pathways in H. pylori and the presence of numerous potential glycoproteins [1]. Recently determined glycosylated proteins in addition to flagellin include catalase and lipopolysaccharide (LPS) biosynthesis enzymes [1]. Avoidance of host immune surveillance is also effected by molecular mimicry and phase variation, two mechanisms relevant to Lewis (Le) antigen presentation on the bacterial cell surface. An additional Le gene (jhp0562) has recently been characterized and found to contribute to both Type 1 and Type 2 pathways of Le synthesis [2]. Moreover, homology between jhp0562 and the downstream jhp0563, encoding β-(1,3)galT, promotes intragenomic recombination, increasing the diversity

of Le phenotypes through the generation of chimeric alleles. Intragenomic selleck chemicals llc recombination likely also learn more accounts for the absence/loss of jhp0562 in some strains and the size heterogeneity of jhp0562 alleles in different geographic strain populations [3]. Molecular mimicry similarly defines the mechanism of immune evasion effected by the variable O-antigen moiety of LPS. Modifications of the LPS lipid A domain that reduce overall negative charge also provide resistance to host cell-lytic cationic antimicrobial peptides (CAMPs). Recent work has identified that dephosphorylation of lipid A is a critical determinant in CAMP resistance [4]. Characterization of the phosphatase

enzymes involved has shown that lipid A dephosphorylation also attenuates the activation of TLR4 thereby reducing host clearance and promoting colonization. In addition to variable surface presentation, the characteristic helical shape of H. pylori has also been shown to influence colonization potential. Two further proteins involved in peptidoglycan modification and cell shape determination have been defined in a study that shows the critical importance of cell shape for motility and penetration of H. pylori within a viscous medium such as gastric mucous [5]. Helicobacter pylori also colonizes the epithelial cell surface from where essential micronutrients such as iron are acquired to support microcolony survival. It is now demonstrated that microcolonies utilize host holotransferrin (iron-saturated transferrin) as an iron source by inducing mislocalization of the basolateral transferrin receptor to the apical surface [6].

miRNA profiles of these samples brought two important insights to the understanding of hepatocarcinogenesis. First, we found that

miRNA deregulation is an early event in which discernible difference was observed between miRNA profiles of primary HCCs and nontumorous liver through clustering analysis. However, no major change was observed between the miRNA profiles of primary HCCs and venous metastases. Second, unlike other cancers, no global miRNA down-regulation was detected Selleckchem Acalabrutinib in primary HCCs. Instead, marked global miRNA down-regulation was detected in venous metastases, and this global miRNA down-regulation could exacerbate the preexisting miRNA deregulation in primary HCCs and facilitate metastasis formation. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; miRNA, find more microRNA; PCR, polymerase chain reaction; snoRNA, small nucleolar RNA; TLDA, TaqMan Low-Density Array. Twenty advanced HCC cases with intrahepatic metastasis as diagnosed with the presence of venous thrombi were selected from a large cohort of approximately 400 HCC patients who underwent curative surgical resection at Queen Mary Hospital, Hong Kong, between 1999 and 2009. Formalin-fixed and paraffin-embedded sections were retrieved from these cases, and the presence of venous thrombi was reviewed by an experienced liver pathologist (IOLN). In our

center, HCCs with gross tumor thrombosis in the portal vein are often inoperable. We therefore selected only those cases in which the venous thrombi were large selleck chemical enough for microdissection. Twenty HCC cases with medium-sized (3-10 mm) HCC thrombi were selected for this study. All patients were of Chinese origin, with a mean age of 51.5 years; 19 were male and one was female. Eighteen patients had chronic hepatitis B virus (HBV) infection, as shown by the positive serum HBV surface antigen status, and the remaining two patients had chronic hepatitis C viral (HCV) infection, as shown by the positive serum anti-HCV status. There were no patients with both HBV and HCV infection. Liver cirrhosis

was present in 13 patients. The demographic data and clinicopathological features of the patients are described in Supporting Table 1. Use of human samples was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Paraffin sections were cut at a thickness of 4 μm, dewaxed, rehydrated, and lightly stained with hematoxylin. Nontumorous livers and their corresponding primary HCC tissues and venous thrombi were examined and microdissected with a 25-gauge needle under a dissecting microscope as described. 11, 12 Four to eight consecutive tissue sections were cut in each case to obtain enough microdissection material for further evaluation. miRNA extraction was performed with an miRNeasy FFPE kit (Qiagen, Valencia, CA).

UBXD8 KO mice showed a significant decrease in the VLDL-TG secretion in comparison to WT mice (553 mg/dl/h vs. 739 mg/dl/h, P=0.006). (5) The

Apo B secretion was directly measured by using primary hepatocytes from WT and KO mice. Hepatocytes of KO mice secreted a significantly less amount of ApoB than hepatocytes of WT mice. The decrease of ApoB secretion in hepatocytes of KO mice was more evident when 0.4 mM oleic acid was added to the culture medium. [Conclusion] The VLDL secretion in hepatocytes is known to be regulated mainly by posttrans-lational Venetoclax solubility dmso degradation of ApoB. The present study showed that UBXD8 plays a critical role in the regulation of VLDL secretion in mouse liver in vivo and that depletion of UBXD8 causes a decrease of VLDL secretion and steatosis. Dinaciclib cell line Interestingly, UBXD8-KO mice on the high-fat diet showed

macrovesicular steatosis mainly in zone 1. This is in contrast with non-alcoholic fatty liver disease, which primarily presents steatosis in zone 3. The unique phenotype of UBXD8-KO mice warrants further studies to elucidate the mechanism behind steatosis. Disclosures: Hidemi Goto – Grant/Research Support: MSD, Roche, Bayer, Bristol-Myers, Eisai, Ajinomoto, Otsuka, Astra, Tanabe The following people have nothing to disclose: Norihiro Imai, Michitaka Suzuki, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Kazuhiko Hayashi, Masatoshi Ishi-gami, Toyoshi Fujimoto Background: see more Fatty liver is associated with ER stress and activation of the hepatic Unfolded Protein Response (UPR), including increased expression of the UPR regulator Xbp1s. Reduced hepatic expression of human XBP1s is associated with NASH compared to bland NAFLD (Gastro 2008) and feeding a high fat diet with high fructose (corn syrup equivalent) to mice has been shown to cause progressive steatohepatitis (AJP, 2011; AJP 2008). The aims of this study are to examine the role of Xbp1 in non-alcoholic fatty liver injury and fatty acid-induced cell injury. Methods: We have developed hepatocyte-specific Xbp1-deficient (Xbp1−/−) mice. A high fat western diet (AIN-76, TestDiet) and drinking

water with 55% fructose and 45% glucose (HFD/HF) (high fructose corn syrup equivalent) were fed to Xbp1−/− and Xbp1f/f control mice for 4 weeks. We performed RNA-Seq and real-time PCR on liver mRNA. We also assayed serum ALT, glucose, hepatic TG and histology. For in vitro study, we generated stable XBP1-knockdown Huh7 cells (Huh7/KD) and scramble Huh7 control cells (Huh7/SCR) and treated them with 400 palmitic acid (PA) for 24 hrs. Cell injury was measured by LDH and caspase 3/7 activity assays. Gene and protein expression was examined by real-time PCR and western blotting. Results: Xbp1−/− mice exhibited higher serum ALT levels 4 weeks after HFD/HF feeding compared to Xbp1f/f controls (70 ± 10 vs 23 ± 2 U/L, p<0.002).