The study of hepatocytes derived from AAT mutant human induced pl

The study of hepatocytes derived from AAT mutant human induced pluripotent stem cells (hIPSC) may overcome this limitation by identifying cellular phenotypes that correlate with clinical severity of disease in existing AAT patients. For this purpose, we have generated hIPSC lines from AAT patients (ZZ) with variable degrees of liver disease, including those without evidence of liver damage and those who have suffered a more aggressive course leading to end stage

liver disease. We are using control and AAT hIPSC-derived hepatocyte like cells (HLCs) to probe the hypothesis that the significant heterogeneity seen in disease progression due to AAT ZZ mutations is related to genetically determined variability of fundamental biological hepatocyte processes involved in cellular selleck inhibitor disposal, stress response, and cell survival pathways. Prior data obtained in mouse and cell line models has shown that autophagy may act as a primary route of intracellular degradation of mutant AAT

protein. Although traditionally regarded as a cellular adaptive process triggered by nutrient deprivation, autophagy in hepatocytes may also provide an important hepatoprotective buy C646 mechanism. Our preliminary results show that HLCs derived from AAT mutant patients with no evidence of liver disease (AAT NLD) have increased activation of autophagy at baseline compared to AAT mutants with severe liver disease (AAT LD). Our data supports a role for autophagy as a potential modifier in the pathobiology of AAT related liver disease and opens the way for mechanistic studies

involving this and other basic biological pathways that may modulate hepatic injury in AAT. Our studies can impact the way we approach AAT deficiency: 1) by developing predictive diagnostics through discovery of biomarkers that identify patients at risk for severe liver disease, and 2) by promoting therapeutic candidate discovery through validation of new or existing therapeutic targets in live human hepatocytes. Disclosures: The following people have nothing to disclose: Tamara Taketani, Maria P. Ordonez, Lawrence S. Reverse transcriptase Goldstein Background: Controlled clinical trials have shown that vitamin E improves liver histology and biochemical profiles in patients with nonalcoholic steatohepatitis. However, its effect in overall NAFLD patients has not been fully elucidated. In this study, we sought to determine the short-term effect of vitamin E, off-treatment durability of response, and predicting factors for vitamin E response in NAFLD patients. Methods: A cohort of 1953 NAFLD patients who visited our outpatient clinic between Jan. 2005 and Mar. 2013 was constructed by using the electronic medical record system (BESTCARE). After excluding comor-bid liver diseases, 257 patients who received vitamin E and 416 control patients were matched for propensity scores. The matched covariates included age, sex, BMI, AST, ALT, presence of DM or dyslipidemia.

54 It could be a consequence of altered blood-brain barrier, decr

54 It could be a consequence of altered blood-brain barrier, decreased expression

of LEPRb, or decreased LEPRb signaling via Jak-2-Stat3 due to an imbalance between expression of negative regulators of leptin sensitivity (suppressors of cytokine signaling [SOCS] proteins, protein tyrosine phosphatase 1B [PTP1B] and SH domain phoshatase 2), and of cellular adaptor molecules, such as SH2B1, which facilitates leptin signaling (Fig. 3).54 Another possibility has recently come to light—requirement of Bardet-Biedl proteins for LEPR signaling, inferring a possible Ixazomib molecular weight role of receptor scaffold assembly on neuronal primary cilia.55 Neurons express a primary cilium, on which is assembled a range of receptors involved in development (e.g. Hedgehog), neurohormonal regulation (somatostatin receptor 3) and appetite (melanin-concentrating hormone receptor 1 [MC-1R], and LEPRb).55–59 FDA approved Drug Library order Primary cilia are found on many cells, but not hepatocytes. They may act as sensory

‘cell antennae’, coordinating inter-cellular communications via receptor clustering and signalling.56–58 Bardet-Biedl syndrome (BBS) is the archetypical example of a ciliopathy with profound appetite dysregulation.59 Like children with leptin deficiency or LEPRb mutations,50–53 BBS children are unable to resist the drive to eat, becoming massively obese at an early age, and about half develop T2D and metabolic syndrome.59,60 Multiple mutations of the BBS gene have been described;55,59 in mice, at least four genotypes are associated with defective LEPRb signaling.55,59 Another childhood obesity syndrome that may be ascribed to a ciliopathy is Alström syndrome.61,62 In addition to their respective specific features (skeletal, retinal, renal and hepatobiliary fibrocystic abnormalities, hearing defects and male infertility), BBS and Alström syndrome are both associated with hyperphagic obesity, early onset of insulin resistance, T2D and (best described for Alström syndrome) severe fatty liver disease leading to cirrhosis.63 An animal model of Alström syndrome,

check details the foz/foz mouse (which carries a mutation of the gene for basal body protein, Alms1), develops NAFLD.64 Further, environmental factors affect expression of liver pathology, so that mice fed chow develop only steatosis, whereas those fed a high fat diet develop NASH with fibrosis.64,65 An additional exciting finding is that pre-adipocytes also express primary cilia,66,67 and these play a role in their capacity to differentiate and form triglyceride-storing adipocytes and secrete adiponectin. Further studies should explore whether the problem of restricted adipose expansion in metabolic syndrome and NASH (discussed later) could actually be due to innate properties of pre-adipocytes/adipocyte differentiation rather than ‘adipose exhaustion’.

[6] AZ

[6] Selleckchem MAPK Inhibitor Library Previously, the frequencies of L31M/V/F and Y93H were reported to be 2.7% and 8.2%, respectively, with direct sequencing in genotype

1b daclatasvir treatment-naïve Japanese patients (n = 294) and this was comparable with the frequency (3.8% and 8.3%, respectively) in genotype 1b patients, determined from the European HCV database (n = 1796).[6, 25] Among the regimens including daclatasvir for genotype 1b HCV infection, until now, only the result of a phase II trial of daclatasvir/asunaprevir therapy for 43 patients has been reported.[8, 9] In that study, the pretreatment presence of HCV carrying Y93H was significantly associated with non-SVR to that regimen and, moreover, that viruses carrying mutations in both regions of NS5A (L31M/V/F and Y93H) and of NS3 (D168A/V) emerged in most of the non-SVR patients after virological failure. In our study, the presence of L31M/V/F and Y93H mutations in daclatasvir treatment-naïve genotype 1b patients was comparable to a previous study which involved direct sequencing, when a cut-off value was introduced to our deep sequencing data, although the prevalence of NS5A mutants changed

depending on the cut-off value. However, deep sequencing analysis revealed that NS5A L31M/V/F and Y93H mutations were detectable in 13 (11.8%) and 34 of the 110 (30.9%) patients, respectively, Proteasome inhibitor above the background error rate of 0.1% and significantly more frequently than detected by direct sequencing. These results demonstrate BCKDHB that deep sequencing is useful for the detection of viral mutants present as minor variants. Do HCV populations with Y93H present as minor variants have any association with clinical characteristics? Interestingly, univariate analysis based on the relationship between the presence of the Y93H variant and clinical factors or factors determining treatment efficacy to PEG IFN/RBV combination therapy extracted three significant factors: the IL28B SNP, core a.a. 70 and the IRRDR (Table 4). All these factors were associated with a favorable response to PEG IFN/RBV combination therapy in the group with the Y93H-resistance mutation.[26] Despite

that the difference did not reach statistical significance, the number of substitutions in the ISDR also tended to be higher in the group with the Y93H mutation, similar to the IRRDR. It was quite intriguing that multivariate analysis of the presence of Y93H extracted the IL28B major type, the SNP was significantly associated with favorable IFN responses, as an independent factor (Table 4). On the other hand, because it is known that the IL28B SNP is closely linked with core a.a. 70, it is assumed that core 70R should be observed more frequently in the group with Y93H.[16] Then, do NS5A resistant variants with Y93H that are present prior to treatment affect the response to daclatasvir treatment? At present, in genotype 1b infection, daclatasvir is scheduled to be used in combination with other DAA but not with IFN.

5-FGR cells (Fig 4D), consistent with our observations in Huh7 c

5-FGR cells (Fig. 4D), consistent with our observations in Huh7 cells (Fig. 2). This down-regulation

in HCV expression correlated with decreased mRNA levels of PPAR-α and ANGPTL3 (Fig. 4E). Our results confirm that miR-27 overexpression selleck chemical inhibits HCV replication. Interestingly, we also observed down-regulation of retinoid X receptor alpha (RXR-α), a previously reported target of miR-27 (Supporting Fig. S9A,B).[31] This protein interacts with several nuclear receptors, including PPAR-α, to regulate liver lipid biosynthesis. Therefore, we examined the functional relevance of miR-27-mediated repression of RXR-α expression on HCV replication and lipid metabolism. We performed CARS imaging on Huh7 cells treated with an RXR-α antagonist, UVI-3003, which inhibits the RXR-α’s interactions with all other nuclear receptors.[32] Huh7 cells treated with this

drug displayed no change in hepatic lipid content (Supporting Fig. S9C). Additionally, RXR-α antagonism in Huh7.5-FGR cells produced no changes in HCV levels. We were also interested in how miR-27′s regulation of PPAR-α signaling would affect viral infectivity. Selleckchem BMN 673 Previous work suggested that increased PPAR-α expression blocks assembly of HCV infectious particles.[33] Huh7.5 cells were cotransfected with JFH-1T RNA and miR-27b mimics and inhibitors, and intracellular HCV RNA levels were measured by qRT-PCR. Neither the miR-27

mimic nor the miR-27 inhibitor had any effect on JFH-1T replication (Supporting Fig. 10), suggesting that miR-27b overexpression has a genotype-specific effect on HCV replication. On the other hand, miR-27b inhibition resulted in a very modest decrease in secretion of infectious HCV, while miR-27b overexpression had no effect on secreted virus’ infectivity, consistent with PPAR-α’s previously reported antiviral role in HCV secretion.[33] Independent of miR-27′s effects on the viral lifecycle, its conserved induction across HCV genotypes manifests globally as a contributor to hepatic steatosis and thus to HCV-associated Meloxicam liver disease. We continued our evaluation of miR-27 expression in a small animal model of acute HCV infection, using the humanized SCID-beige/Alb-uPa mouse model.[34] We infected the chimeric mice with genotype 1a and 2b clinical isolates of HCV (Supporting Fig. S11). qRT-PCR analysis of miR-27b levels revealed a 2.9-fold up-regulation in miR-27b levels 7 weeks postinfection (Fig. 5A). This increase was conserved across both HCV genotypes examined. There was also a 2.0-fold increase in miR-27a levels (Fig. 5B). Oil Red O staining of lipids in the chimeric liver’s human hepatocytes revealed a correlation between cellular lipid levels and miR-27 expression in mice (Fig. 5C), and provides further support for our CARS microscopy results in cell culture experiments.

BA, bile acids; BSEP, bile salt export pump; CSA, cyclosporine A;

BA, bile acids; BSEP, bile salt export pump; CSA, cyclosporine A; CPZ, chlorpromazine; DHE, dihydroethidium; H2-DCFDA, 2′,7′-dichlorodihydrofluorescein; MTT, methylthiazoletetrazolium; NAC: N-acetyl-cysteine; NTCP, Na+-dependent taurocholic cotransporting polypeptide; ROS: reactive oxygen species; RT-qPCR: real-time quantitative polymerase chain reaction;

SA, salicylic acid; TA: taurocholic acid. CPZ, cholic and chenodeoxycholic acids, salicylic acid Copanlisib (SA), cyclosporine A (CSA), methylthiazoletetrazolium (MTT), N-acetyl-cysteine (NAC), and 6β-hydroxytestosterone were purchased from Sigma (St. Quentin Fallavier, France). Dihydroethidium (DHE), 2′,7′-dichlorodihydrofluorescein (H2-DCFDA), and JC-1 dye were from Invitrogen-Molecular Probe. [3H]-Taurocholic acid was from Perkin Elmer (Boston, MA). HepaRG cells were seeded at a density of 2.6 × 104 cells/cm2 in Williams E medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin,

100 mg/mL strep tomycin, 5 mg/mL insulin, 2 mM glutamine, and 50 mM hydrocortisone hemisuccinate.21 After 2 weeks, HepaRG cells were shifted to the same medium supplemented with 2% dimethyl sulfoxide for a further 2 weeks in order to obtain BMS-354825 mw confluent differentiated cultures with maximum functional activities. At this time, these cultures contained hepatocyte-like and progenitors/primitive biliary-like cells.21 Cytotoxicity of CPZ and BA was evaluated by the MTT colorimetric assay.18 Mitochondrial membrane potential was analyzed using the JC-1 dye.22 F-actin was localized using a phalloidin-fluoprobe.22 Superoxide anions were detected by DHE staining. Ponatinib Cells were incubated with 2 μM DHE and 0.5 μg/mL Hoechst for 30 minutes at 37°C. They were then washed with chilled phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde, and examined under fluorescence microscopy. Hydrogen peroxide generation was determined by the H2-DCFDA assay. Cells were incubated for 2 hours at 37°C with 5 μM

H2-DCFDA; then they were washed with cold PBS, and scraped in potassium buffer (10 mM, pH 7.4) / methanol (v/v) completed with Triton X-100 (0.1%). Fluorescence intensity of cell extracts was determined by spectrofluorimetry using excitation/emission wavelengths of 498/520 nm. Total RNA was extracted from 106 HepaRG cells with the SV total RNA isolation system (Promega). RNAs were reverse-transcribed into cDNA and RT-qPCR was performed using a SYBR Green mix. Primer sequences are listed in Supporting Table 1. Activity of the NTCP transporter was estimated through determination of sodium-dependent intracellular accumulation of radiolabeled TA.20 Cells were first exposed to [3H]-TA for 30 minutes, then washed with PBS and incubated with or without CPZ at different timepoints (from 0 to 6 hours) in a standard buffer with Ca2+ and Mg2+.

The six most intense peptides were fragmented, and the MS1 spectr

The six most intense peptides were fragmented, and the MS1 spectra were acquired at a resolution of 60,000. Data mining was performed against the rat UniProtKB data bank, using Proteome

Discoverer 1.1 software (Thermo Instruments), with an accuracy of less than 5 ppm for parent ions and 0.8 Da for fragments. All the proteins thus identified were analyzed using Pantherd software to determine their gene ontology parameters. Biological and histological features of the patients at the diagnosis of acute hepatitis are reported in Table 1. Mean values for total bilirubin, gamma-glutamyl transferase (GGT), and aminoaspartate transferase (AST) levels, as well as the prothrombin time, were, respectively, 121 µmol/L (range, 29-270), 933 IU/L (range, 455-1,968), 1,438 IU/L (range, 538–2,900), and 74% (range, 37-100). IgG levels were KU-60019 order high in P1 (24.5 g/L) and P5 (24.4 g/L), but normal in the other patients. Pathological examination revealed features of acute hepatitis with interface (n = 4) and lobular (n = 4) necroinflammatory activity. An abundant inflammatory infiltrate, including plasmocytes, was present in three patients (P1, P3 and P5) (Fig. 1). During the initial presentation, fibrosis selleck inhibitor was mild or absent in P1, P3, P4 and P5, and advanced in P2. There was no evidence of pathological features of GVHD or veno-occlusive disease. Moreover, at the onset of liver

dysfunction, no extrahepatic symptoms suggestive of GVHD could be detected. In the control groups, the histological pattern of acetaminophen hepatitis differed markedly from

the pattern described above (Supporting Fig. 1). Necrosis was the sole feature observed, without any lymphoplasmocytic infiltrate. With respect SDHB to autoantibody detection, no patient was positive for anti-SMA, anti-LKM1, or anti-LC1 before and at the onset of hepatic dysfunction. ANA were negative in all patients before hepatic disease and remained negative in P1, P4, and P5, although becoming positive in P2 and P3 (1:80 and 1:640, respectively). All viral markers tested, namely HAV, HBV, HCV, HEV, CMV, EBV, HHV6, and HSV, were negative in patients P2, P3, P4, and P5 before BMT and remained so after the onset of hepatic dysfunction. In P1, although the HCV test was positive before BMT, no HCV RNA could be detected by PCR. Immunoblottings performed on cellular fractions displayed very few common stained bands between patients P1-P3 and the two control groups (Supporting Fig. 2). A comparison of 2D immunoblotting patterns showed that immunoreactive spots were more numerous and more intensely stained by the three sera collected at the onset of the hepatic dysfunction than by those collected before, regardless of the type of liver subfraction used as the antigen (Fig. 2). Moreover, a marked patient-related heterogeneity of the patterns was noted (Fig. 3). A total of 259 spots only present at the time of onset of liver dysfunction were detected (Supporting Fig.

Liver volume assessed by magnetic resonance imaging (MRI) decreas

Liver volume assessed by magnetic resonance imaging (MRI) decreased by 4.9% with octreotide

and increased by 0.9% with placebo.5 These results are in line with a post-hoc analysis of a crossover study that treated 12 ADPKD patients with polycystic livers for 6 months with long-acting octreotide LAR 40 mg each month. Liver volume decreased by 4.4% during octreotide administration, whereas it increased by 1.2% with placebo.6 The volume-reducing effect of octreotide is not dependent on its formulation. Short-acting octreotide administered at a dose of 100 μg three times daily subcutaneously Selleck Pexidartinib for 70-180 days in eight patients (seven ADPKD; one PCLD) resulted in a median reduction of liver volume by 3.0%55 (Fig. 5). The randomized clinical studies documented that the beneficial effect of somatostatin analogs was associated with improved general health perception.4, 5 Somatostatin analogs are well tolerated. Side effects such as diarrhea and abdominal

cramps occur after the first injections but disappear after prolonged use. Another medical option that has gained popularity are mammalian target of rapamycin (mTOR) inhibitors. This class of drugs has strong antiproliferative effects learn more and has become an integral part of immunosuppressive therapy after solid organ transplantation.56 mTOR is upregulated in animal models of polycystic AZD9291 kidney disease and inhibition slows disease progression.57, 58 In a trial with 16 ADPKD patients who had polycystic livers after renal transplantation the mTOR inhibitor sirolimus reduced liver volume by 11.9% when given for an average of 19.4 months, whereas tacrolimus caused an increase of 14.2%.19 There are still many outstanding questions. It is unknown why some patients respond well, whereas others do not, but it appears that larger livers respond better to treatment than smaller livers.4 The most important issue is whether the beneficial effect is maintained with prolonged

therapy. Answers might come from ongoing trials that evaluate the effect of a 3-year treatment.6 Finally, whereas somatostatin analogs are well tolerated, the side-effect profile is less acceptable with mTOR inhibitors.59, 60 PLD is a progressive disease, and a substantial minority of patients will develop severe symptoms. Invasive procedures may provide relief through liver volume reduction in selected cases. Apart from liver transplantation, none of the currently available options have been shown to change the natural course of the disease. In addition, there is no consensus on the optimal timing or optimal procedure to be carried out. Although all procedures listed here are technically feasible, they do carry the risk of considerable morbidity, and potential benefits should be weighed carefully against the drawbacks of the individual procedures.

Use of these agents has been studied across a variety of indicati

Use of these agents has been studied across a variety of indications and populations, and at different stages in the disease course. Failure to respond or loss of response can result from different causes, and can be medically managed in many cases. More research on the pleiotropic

CP-868596 molecular weight effects, safety of biological agents and biomarkers in the prediction of response will provide a sounder basis for individually directing therapy. Adverse events such as opportunistic infection and malignancy can occur, and screening prior to therapy and discussion on risk-benefit of the various management options are important. Cost of these medications especially with maintenance therapy remains an important issue in many Asia-Pacific countries. New and more specific agents will better target therapy and minimize adverse events. Biological agents” describe a class of substances manufactured from a living organism

or by recombinant technology that includes peptides, monoclonal antibodies, fusion proteins and antisense oligonucleotides that bind to nucleic acids.1 In inflammatory bowel diseases (IBD), this group of drugs manipulates key molecules that are involved in the induction and maintenance of intestinal inflammation. They are expensive and risk adverse effects, but this is counterpoised by their superiority to conventional immunosuppressive agents in their efficacy to decrease refractory inflammation, induce mucosal healing, and reduce rates of surgical intervention and long-term complications. Pexidartinib solubility dmso Molecules Interleukin-2 receptor and targets.  An evolving understanding of the pathogenesis of IBD has identified several immunomodulatory therapeutic targets. In Crohn’s disease (CD), T helper 1 (Th1) and the distinctively different T helper 17 (Th17) cells mediate proinflammatory cytokines.2 Both Th1 and Th17 pathways lead to increases in circulatory and tissue

tumor necrosis factor (TNF)-α, the target of anti-TNF-α therapy in both CD and ulcerative colitis (UC).1 Three anti-TNF agents are used in the treatment of IBD. Infliximab is a murine-human chimeric monoclonal antibody, adalimumab is a humanized monoclonal antibody, and certolizumab pegol is a pegylated monoclonal antigen binding fragment (Fab’) to TNF-α. Other anti-TNF-α biological agents currently in clinical trial include golimumab, and this may offer an additional therapeutic option. The alternative Th17 pathway involves interleukin (IL)-23, liberating IL-17A, IL-17F, IL-22 and TNF-α. IL-23 receptor polymorphism is known to protect against the development of CD, and other polymorphisms of the pathway are linked to the development of inflammatory diseases such as ankylosing spondylitis and Grave’s ophthalmopathy.3 Therapeutic neutralization of human IL-12/23 using ustekinumab and briakinumab, approved or are under trial for psoriasis, are currently under evaluation for IBD.

Interestingly, ApoE−/−/5-LO−/− mice showed reduced serum glucose

Interestingly, ApoE−/−/5-LO−/− mice showed reduced serum glucose concentrations compared with both WT and ApoE−/− mice (Supporting Table 1). The expression

of specific LTB4 and LTD4 receptors (BLT1 and CysLT1) was up-regulated in liver samples from ApoE−/− mice and was not further modified by disruption of the 5-LO gene Alox5 (data not shown). Consistent with the presence of histological and biochemical evidences of liver injury, ApoE−/− mice exhibited increased hepatic expression of TNF-α (Fig. 2A), interleukin (IL)-18 SB525334 nmr (Fig. 2B) and monocyte chemoattractant protein-1 (MCP-1) (Fig. 2C). In agreement with the protective effects exerted by deletion of 5-LO in ApoE−/− mice, the expression of these proinflammatory cytokines Dabrafenib ic50 was significantly reduced in ApoE−/−/5-LO−/− mice (Fig. 2A-C). IL-6 expression remained unchanged (Fig. 2D). On the other hand, the expression of peroxisome proliferator-activated receptor (PPAR) γ and insulin receptor substrate

(IRS)-2 was similar in the three groups of mice (Fig. 2E,F). In contrast, the expression of the glucose transporter Glut-2 was significantly increased in ApoE−/−/5-LO−/− mice (Fig. 2G), although the measurement of JNK phosphorylation, a direct marker of insulin resistance,21 indicated no changes in hepatic insulin sensitivity (Fig. 2H). The expression of genes involved in hepatic lipogenesis (sterol regulatory element-binding protein-1c and fatty acid synthase) and fatty acid oxidation (i.e. PPARα) remained unchanged (data not shown). Because adipose tissue–derived adipokines have a direct influence on the progression of liver injury in fatty liver disease,22, 23 we next

examined the expression of adipose tissue–specific genes in the three groups of mice included in the study. A significant up-regulation of the anti-inflammatory adipokine adiponectin (Fig. 3A) in parallel with a reduction of the proinflammatory adipokines MCP-1 and IL-6 (Fig. 3B,C) was observed in adipose tissue from ApoE−/−/5-LO−/− mice. No changes in the expression of TNF-α (Fig. 3D) and resistin (data not shown) were observed. Moreover, ApoE−/−/5-LO−/− mice exhibited a remarkable up-regulation of PPARγ and IRS-1 expression in the adipose tissue, two genes that regulate complex pathways in lipid and carbohydrate metabolism (Fig. 3E,F). Moreover, the measurement of JNK TCL phosphorylation in adipose tissue revealed significant insulin resistance in ApoE−/− mice, an effect that was abrogated by the genetic deletion of the 5-LO gene in ApoE−/−/5-LO−/− mice (Fig. 3H). No changes in Glut-4 (Fig. 3G) and sterol regulatory element-binding protein-1c and fatty acid synthase (data not shown) were observed. To further assess the contribution of 5-LO products to the increased susceptibility to liver injury displayed by ApoE−/− mice, we evaluated in vitro the extent of damage in hepatocytes isolated from the three groups of mice of the study.

Reporter assays showed that

Reporter assays showed that CHIR-99021 solubility dmso the activation of LXRs significantly reduced the transcriptional activity of FOXM1 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated that LXRα but not LXRβ could

bind to an inverted repeat IR2 (-52CCGTCAcgTGACCT-39) in the promoter region of FOXM1 gene. Moreover, FOXM1 expression in liver tissues was also inhibited in the mice fed with LXRs agonists. Conclusion: Taken together, we conclude that LXRα but not LXRβ functions as a transcriptional repressor for the expression of FOXM1. The pathway “LXRα-FOXM1-Cyclin D1/B1” is a novel mechanism by which LXRs suppress the proliferation of HCC cells, suggesting that the pathway may be a novel target for the treatment of HCC. Key Word(s): 1. LXRs; 2. FOXM1; 3. proliferation, cycle; 4. HCC; Presenting Author: QIANGJIAN WANG Additional Authors: JUNLI LAO, XIONGWEN ZOU, YUAN HUANG Corresponding Author:

YUAN HUANG Affiliations: The Second Affiliated Hospital of Nanchang University; the first affiliated hospital, liaoning medical schoo Objective: To assess the therapeutic effect of metformin combined with reduced glutathione on patients with non-alcoholic fatty liver disease. HKI-272 cell line Methods: 150 patients with non-alcoholic fatty liver disease were randomly divided into three groups, control group, low-dose group and high-dose group, each is 50 patients. Patients in low-dose group were treated with

metformin Methisazone (250 mg tid) combined with reduced glutathione (0.1 g tid) and patients in high-dose group were treated with metformin (500 mg tid) combined with reduced glutathione (0.1 g tid), while in control group treated with metformin (250 mg tid) for consecutive 6 months. Liver function indexes (ALT, AST, r-GT) and lipid levels (CH, TG, HDL, LDL) were compared before and after treatment. Side-effect was also observed during the experiment. Results: The liver function indexes and lipid levels of three groups were all obviously changed compared with pretherapy at the end point. It of high-dose and low-dose groups were all changed than control group (P < 0.05). And no severe side-effects occurred during the experiment. Conclusion: Metformin combined with reduced glutathione is an effective and safe remedy for treatment of non-alcoholic fatty liver disease, and with the increase dosage of metformin, the therapeutic effect increased. Key Word(s): 1. NAFLD; 2. metformin; 3. reduced glutathione; Presenting Author: LI CHANGPING Additional Authors: HESHUANG YAN Corresponding Author: LI CHANGPING Affiliations: affliated hospital Objective: To investigate the role of hepatocyte apoptosis, related factors: Fas, FasL, Bcl-2, Bax proteins and Caspase-8 mRNA in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in rats.