7% (18/19) The mean time required to reach

7% (18/19). The mean time required to reach click here the blind end was 34.0 min. The diagnostic success rate was 89.5% (17/19). The mean procedure time was 72.6 min. The success rate of overall modified SBE-assisted ERC was 78.9% (15/19). The complication rate was 26% (hyperamylasemia in four patients). Conclusion: Diagnostic and therapeutic ERC using our novel approach of modifying SBE without the use of special or prototype instrumentation or enteroscope replacement is safe and effective. Key Word(s): 1. single-balloon enteroscopy; 2. endoscopic retrograde cholangiography (ERC); 3. roux-en-y reconstruction; 4. billroth-II gastrectomy Presenting Author: AKIRA TERAMOTO Additional Authors:

KASEN KOBASHIKAWA, KOTA TOMISATO, AKIYUKI KONDO, ATSUSHI IRAHA, SHOKO NAKAMURA, SHINOBU MATSUKAWA, AKIRA YABUTANI, MASAMOTO NAKAMURA, TOMOKUNI NAKAYOSHI, NOBUFUMI UCHIMA, FUKUNORI KINJYO, SHINICHIRO KAMEYAMA, TOMONARI ISHIMINE, TSUTOMU ISA, AKIO YANAGISAWA Corresponding Author: AKIRA TERAMOTO Affiliations: Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Kyoto Prefectural

Hospital of Medicine Objective: Introduction: Inflammatory pseudo-tumor (IPT) is an uncommon cause of cholangitis, composed of inflammatory cell infiltration and proliferating

fibrous tissues. Even with imaging devices, CDK inhibitor ERCP and cytodiagnosis that we have today, it is difficult to deny malignant neoplasm and the final diagnosis is relied on pathological outcome of surgically dissected specimen in many cases. Methods: Presentation of case: A 35year-old-man has been followed at our hospital since 2009 for chronic liver dysfunction. The cause of liver dysfunction was not identified from his hepatic biopsy and serum tests. In 2013, he has presented to our hospital with complaint of epigastric pain and ultrasonography showed upper bile duct dilation up to 8 mm. Stenosis with thickened biliary wall was located at lower bile duct using enhanced CT and MRCP, Tenoxicam and this was seen as a hypo-echoic tumor-like lesion in EUS. ERCP was performed and there was no malformation of Vater’s papilla or malfusion of pancreaticobiliary ducts. Main findings of cholangiography were (A) biliary stenosis at mid ∼ lower part of common bile duct, (B) caliber variations at the base of right hepatic ducts. Biopsy forceps and cytodiagnosis brush were used for biopsy at (A), and eight bile specimen were collected from ENBD but malignancy was not proven pathologically. Pancreaticoduodenectomy was conducted as the patient gave his consent to the proposal of surgery. The pathological outcome was consistent with chronic cholangitis with small duct hyperplasia, showing the nature of IPT.

Purely arterial blood is supplied by the biliary plexus Focal is

Purely arterial blood is supplied by the biliary plexus. Focal ischemia can have severe effects on the biliary epithelium and its secretory function. The detrimental effect of ischemia on cholangiocytes and formation of ischemia-induced portal casts28 could be explained by a collapse of the biliary HCO umbrella potentiating bile acid toxicity. Biliary HCO formation is under tight control of local

factors such as bile salts or purinergic agonists as well as of visceral neurohormonal factors including secretin, AZD1208 cholinergic and adrenergic agents, vasoactive intestinal peptide (VIP), glucagon, glucagon-like peptide-1, and somatostatin. We restrict our discussion to local factors Selleck GSI-IX contributing to formation of a stable HCO umbrella. For the role of visceral neurohormonal factors which, like secretin, also may depend on local factors to induce HCO formation,29 we refer to recent reviews on the neurohormonal control of the adaptive cholangiocyte response.30 The bile salt sensing receptor TGR5 (GPBAR-1) is localized on the tip of the cilia of apical mouse and human cholangiocyte membranes31, 32 reaching beyond the hypothetical HCO umbrella, thus sensing real bile composition. An obvious function of luminal bile salt sensing would be to modulate the

cellular defense strategies by varying HCO secretion through direct stimulation of secretory channels or proteins and/or insertion/retrieval of key carriers/channels such as AE2 and cystic fibrosis transmembrane conductance regulator (CFTR).33 Recent in vitro studies strongly support this view: stimulation of TGR5 was shown to increase Cl− secretion of human gallbladder mucosa by way of CFTR in a cAMP-dependent way.34 The reportedly low levels of the apical bile salt transporter expression in cholangiocytes would argue in favour of a sensor function rather than a high throughput transport function of apical bile salt transporter. Rates of HCO formation as the major oxyclozanide human biliary defense mechanism against bile acid

toxicity in the intrahepatic biliary tree would then be under tight control of at least two types of bile acid sensors. Extracellular adenosine triphosphate (ATP) is increasingly recognized as an important signaling molecule in the regulation of bile secretion and composition.35, 36 ATP and its metabolites adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine are present in human bile collected from the common bile duct.37 Cholangiocytes express purinergic receptors from the P2Y family on their membranes and cilia, and these receptors translate the signal of adenosine nucleotides in bile into intracellular cAMP levels as well as changes in cytosolic-free calcium [Ca++]I and activation of different conventional, novel, and atypical protein kinase C (PKC) isoforms.

It plays an important role in the process of maturity and differe

It plays an important role in the process of maturity and differentiation of B cells. There are not available that BAFF expression and the predictive value on treatment outcome in patients with CHIR-99021 in vitro chronic hepatitis C (CHC). Methods: 175 CHC patients were enrolled with PEG-IFNα-2a (180 μg, qw) / RBV (800-1200mg/d) treatment for at least 12w. IL28B SNP rs12979860 and rs8099917 and HCV genotype were detected

at baseline, while serum ALT, AST, TBIL, HCV RNA loads and BAFF levels were detected before and 4w, 12w after treatment. BAFF levels were assessed on 58 health blood donors (HBD). To compare BAFF levels among these three groups, and analyze predictors to RVR in patients after antivirus treatments. Results: 1.BAFF levels in patients with RVR (median 2400.0pg/ml) were higher than that in patients without (median 1731.6pg/ml) and than that in HBD (median 1095.9pg/ml), successively, P<0.05. The lowest BAFF level was 724pg/ml in this study. 2. HCV genotype, IL28BSNP rs12979860 and rs8099917 genotype, HCV RNA and BAFF baseline were included in the logistic regression analysis

and ROC was drawn to evaluate predict value of BAFF to RVR. After calculation IL28B SNP rs12979860 genotype and BAFF become influence factors to RVR. This was a logistic regression equation: Y=2.427-0.001 xBAFF-2.013×lL28BSNP rs12979860 (coded CC Genotype as 1 and non-CC as 0, Y=0.3614 according to the ROC cut-off point) . If a patient with CC genotype or non-CC genotype whose BAFF baseline were above ADP ribosylation factor 52.5pg/ml or 2065.5pg/ml, the AUROC achieved 79.6% (Figure 1). Conclusions: 1. BAFF expression INCB018424 datasheet in patients with hepatitis C-infected is higher than HBD.

2. BAFF is a predictor to RVR in patients with IL28BSNP rs12979860 non-CC genotype after antivirus therapy. There is higher RVR rate in patients with CC genotype regardless of others indexes. Figure l: ROC curve in prediction on BAFF to 1^ R after logistic regression analysis-Note: AUROC curve values (95% CI) were 0.796(0.684-0.908), cut-off point is 0.361, sensitivity is 0.904, specificity is 0-696, negative predictive value is 0.762,.P=0.000 Disclosures: The following people have nothing to disclose: Jing Liu, Zhen Xu, Wen-Xiong Xu, Zhi-Shuo Mo, Xiang Zhu, Zhi-liang Gao Although recent studies indicate that supplementation of vitamin D significantly improves a sustained viral response by IFN-based therapy to chronic hepatitis C, detailed mechanisms for the role of vitamin D are not fully elucidated. Previously, we demonstrated that the metabolite of vitamin D, 25-hydroxyvita-min D, has the direct anti-viral effect against hepatitis C virus (HCV) targeting infectious virus production. Since vitamin D is known to be multi-functional, we reasoned that other anti-viral functions of vitamin D, especially through immunomodulatory activity, should be considered.

Results: We present a case of a 69-year-old male exhibiting vomit

Results: We present a case of a 69-year-old male exhibiting vomiting and dysphagia for one year. DES may lead to severe dysphagia, chest pain, or vomiting. However, these symptoms are not specific enough to diagnose DES in clinical practice, which may delay diagnosis and lead to a worsening of conditions in patients. Conclusion: The hallmark of DES is simultaneous esophageal contractions. The causes

of DES selleck products are still unknown, and the ideal treatment remains to be determined. Key Word(s): 1. esophageal Spasm; 2. case report; 3. literature review; Presenting Author: CHENWEI CHANG Additional Authors: HUANGYU XIE, YE NI, QIANYI TING, ZHANGGUANG BO Corresponding Author: CHENWEI CHANG Affiliations: Department of Gastroenterology, RAD001 supplier The First Affiliated Hospital of Soochow University. Objective: To preliminary analysis the characteristics of change of serum levels of pepsinogen (PG) in gastric cancer, gastric precancerous lesions patients and healthy controls, and to preliminary investigate the relationship between serum PG, Helicobacter pylori (HP) infection with gastric cancer, gastric precancerous lesions. Methods: The serum pepsinogen I and II levels were measured by ELISA in 208 patients with different gastric diseases patients (40 cases of superficial gastritis, 41 cases of gastric ulcer, 46 cases of atrophic gastritis, 26 cases of dysplasia,

55 cases of gastric cancer) and 58 healthy controls. Serum Hp-IgG antibodies was detected by colloidal gold

method. Results: 1) The serum PG I, PG II and PG I/PG II ratio (PGR) in superficial gastritis group were no significantly difference with in healthy controls (P > 0.05). The serum PG I and PG II levels in gastric ulcer group were significantly higher than in healthy controls (P < 0.01), PGR was significantly lower than in healthy controls (P < 0.05). The serum PG I level and PGR in atrophic gastritis group, dysplasia group from and gastric cancer group were significantly lower than in healthy controls (P < 0.01), the serum PG II level was significantly higher than in healthy controls (P < 0.05 or P < 0.01). 2) The PGR in dysplasia group and gastric cancer group were significantly lower than in atrophic gastritis group (P < 0.05 or P < 0.01), but the serum PG I and PG II levels were no significantly difference among the three groups. 3) The areas under the ROC curves performed by the PG I and PGR from healthy controls and gastric cancer group were 0.808 and 0.879, respectively. With serum PG I ≤ 73.14 ng/ml or PGR ≤ 4.79 as the critical value, the sensitivity and specificity to the screening for gastric cancer were 90.9%, 72.4% respectively. 4) There were no difference to the positive rates of HP infection among healthy controls, superficial gastritis, peptic ulcer, atrophic gastritis, dysplasia and gastric cancer (56.9%, 65.0%, 78.0%, 69.6%, 57.

01%) or on water agar with subsequent transfer to CPA (JKI method

01%) or on water agar with subsequent transfer to CPA (JKI method). For single zoospore cultures, 20 ml sterile water was added to a 10-day-old V8 culture. The sporangia suspension was then put at 2–8°C for 1 h to release zoospores. After 30 min at room temperature,

plating was carried out at a concentration of 50 zoospores per ml on V8. The plates were incubated overnight at 20–22°C in the dark, and single zoospore cultures were transferred to new plates. At CRAW, mycelium plugs from V8-cultures were stored in sterile water at 13°C. Between 2002 and 2007, isolates were transferred every 6 months onto fresh medium. From 2008 onwards, they were subcultured yearly. At JKI, long-term storage was carried out on oatmeal Vemurafenib datasheet agar (40 g/l), under paraffin PD-0332991 ic50 oil (16–17°C, in the dark) and on oatmeal agar with glycerine (50 ml/l of a 87% glycerine solution) in liquid nitrogen. New liquid nitrogen and paraffin oil storage cultures were prepared in 2004, 2007 and 2009. At ILVO, isolates were stored in sterile water as described for CRAW but at 4–8°C. Isolates kept under these long-term storage conditions were transferred every 1–3 years. At CRAW and ILVO, mating type determination was carried out using the method of Brasier and Kirk (2004) using

tester strains 2299 (A1) and 3237 (A2) at CRAW and PR/D/02/2084 (A1) and PRI480 (A2) at ILVO. At JKI, crossings were performed on CPA with complementary strains from four heterothallic species (Werres et al. 2001). In 2011, mating type determinations were replicated in each of the three laboratories. In 2006, during a mating type survey performed at CRAW, isolate 2545 (which was reisolated from A. glutinosa sapling inoculated

with the isolate 2338 in 2003) was found to have reverted to A1. In contrast, other isolates derived from isolate 2338 after inoculation on different tree species Pembrolizumab concentration (i.e. isolates 2531, 2533, 2546) were still A2. Isolate 3237 (derived from BBA26/02 and put in the CRAW collection in 2005) conserved its A2 mating type. Isolate 2386 (A1 in 2002) remained A1 (Table 1). In 2011, the mating type of all isolates was identified. Reference A1 isolates BBA27/02 and PR/D/02/2084 were still A1 (Table 1). Isolate 2338 (maintained for 9 years in the CRAW collection and originally A2) was found to be A1. Moreover, BBA26/02, an A2 isolate maintained at JKI since 2003, was also found to be A1. Isolates 3237, 2533, 2546 as well as the two other Belgian EU1 A2 isolates identified in 2003 at ILVO and the American isolates PRI480 and BBA Pr01 were still A2 (Table 1). Six single zoospore cultures were produced from isolate 2338 and from two other strains that conserved their initial A2 mating type (2546 and PR/D/02/2340). All single zoospore cultures displayed the same mating type as their corresponding parental isolate.

2 months versus not reached; recurrence, 87 50% versus 61 3%; P =

2 months versus not reached; recurrence, 87.50% versus 61.3%; P = 0.073) and while there was no significant difference

among recurrence rates of groups I and III (P = 0.241) (Fig. 4B). Compared with group IV, patients in the other three groups had significantly shorter TTR and higher recurrence rates (P < 0.001) (Fig. 4B). The most effective therapeutic options for HCC offering a favorable prognosis are hepatectomy and liver transplantation. However, even such presumably curative surgery does not guarantee full recovery, and this failure is due in large part to the high incidence of recurrence (50%-70% at 5 years).2 The most significant reason for the unsatisfactory therapeutic AG-014699 clinical trial outcome is residual micrometastases formed prior to resection or dissemination of tumor cells during surgical manipulation.25 Unfortunately, routine diagnostic approaches are thus far unable to identify the HCC patient subpopulation at high risk of developing micrometastases preoperatively,17 as well as the tumor cells that escape or invade into peripheral blood during surgery. Recent clinical studies have provided evidence that CTCs may directly participate in the metastasis cascade in various types of malignancies.26

The prognostic significance of CTCs has been widely reported in metastatic breast, colon, and prostate cancers. However, the presence of CTCs in the circulation is a necessary but insufficient condition for the initiation of metastasis, since only a minority of dispersed cells possessing stem cell–like properties Thalidomide is capable this website of reseeding the tissue of origin or metastasizing to distant organs.3, 6 Therefore, identifying the stem cell–like CTC subset with such properties would provide more clinically relevant prognostic

information than total CTC counts. In the present study, we found that patients with preoperative CTC7.5 levels of ≥2 EpCAM+ CTCs suffered significantly earlier recurrence (within 1 year) than patients with lower levels. A preoperative EpCAM+ CTC7.5 ≥2 was significantly associated with aggressive HCC phenotypes. Moreover, EpCAM+ CTCs displayed stem cell–like traits. Based on these data, we inferred that EpCAM+ CTCs with stem cell–like phenotypes might represent a more aggressive subset of CTCs. These cells were more likely to invade the circulatory system, survive, and finally seed in orthotopic or distant sites, leading to local recurrence or distant metastasis. Thus, the preoperative detection of EpCAM+ CTCs might serve as a novel indicator reflecting the micrometastatic status and recurrence risk of HCC patients in a real-time manner, which in turn could provide a therapeutic window and target before the appearance of bona fide recurrence. According to the CSC hypothesis, a small population of cells possessing stem cell–like traits is the driving force of tumor progression and resistance to classical therapies.

Wild fish showed habitat-dependent differences: enlarged telencep

Wild fish showed habitat-dependent differences: enlarged telencephalic lobes and reduced optic tecta were found in fish living in darkness and sulphidic waters, in darkness without hydrogen sulphide or exposed to light and sulphide; fish from the sulphidic cave additionally showed enlarged cerebella. Comparison with common-garden reared fish detected a general decrease in brain size throughout populations in the lab, and little of the brain size divergence between lab-reared ecotypes

that was seen in wild-caught fish. The pronounced differences in brain region volumes between ecotypes in the wild might be interpreted within the framework of mosaic evolution; however, the outcomes of common-garden experiments indicate a high amount learn more of phenotypic plasticity. Our study thus highlights the importance of combining the selleckchem investigation of brain size in wild populations with common-garden experiments for answering questions of brain evolution. “

investigated changes in burrow architecture and fractal dimension across seasons and between the sexes in the solitary East African root rat Tachyoryctes splendens over an entire calendar year. The basic burrow system comprised a main tunnel reticulating into foraging tunnels, a nest consisting of food store chamber, latrine and sleeping area, and a bolt hole. Main tunnel length was strongly affected by sex, and contrary to expectations, it was longer for females mafosfamide than for males (during both the dry and the wet

seasons). The number and the length of foraging tunnels were affected by both sex and season, with females’ burrows having more foraging tunnels than males in both the dry and the wet seasons. Females also had burrows with higher fractal dimension than males, while fractal dimension increased with burrow length for both sexes. We suggest that unlike the solitary bathyergid mole-rats, male T. splendens do not construct larger burrows than females in the search for mates, but rather females have larger burrows with more foraging tunnels resulting from the increased need for provisioning of their young. “
“South American caviomorph rodents comprise four major lineages encompassing wide taxonomic and ecological diversity, but the morphological diversity of their postcranial skeleton has not been thoroughly explored using phylogenetic comparative methods. The main goal of this work is to analyze their humerus using geometric morphometrics in a phylogenetic context and attempt to tease apart the influence of locomotory preferences and shared evolutionary history on morphological variation. We examined 28 genera in 9 families representing all major clades. Humeral shape was captured by 13 landmarks and four semilandmarks in 2D. In the morphospace of the first two principal components, most taxa were located near the origin along both axes. Fossorial octodontoids were apart from this central group.

Blockade of HMGB1-RAGE interaction has been shown to effectively

Blockade of HMGB1-RAGE interaction has been shown to effectively reduce liver damage upon acute injury.14, 15, 49 Unfortunately, Hmgb1−/− mice die at birth50 and, hitherto, no conditional Hmgb1−/− mouse has been established to test whether HMGB1 ablation in check details the Mdr2−/− mouse phenocopies the dKO liver phenotype. Furthermore, it will be of great interest to correlate the expression of RAGE and the abundance of its ligands, in particular HMGB1, with the severity of disease and its clinical outcome in different human liver disorders, and to prove the concept that pharmacological inhibition of RAGE

signaling represents a novel strategy for the prevention of HCC development during early stages of liver injury. We thank Tine Bauer, Angelika Krischke, and Sandra Prokosch for technical support, Prof. George Yeoh (University of Western Australia) and Janina Tirnitz-Parker for BMOL cells, and Valentina Factor (NIH) for the A6 antibody. Additional Supporting Information may be found in the online version of this article. “
“Fafi-Kremer S, Fofana I, Soulier E, Carolla P, Meuleman P, Leroux-Roels G, et al. Viral entry and escape from antibody-mediated neutralization INCB024360 clinical trial influence hepatitis

C virus reinfection in liver transplantation. J Exp Med 2010;207:2019-2031. (Reprinted with permission.) End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the

liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms else of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft. Recurrent hepatitis C after orthotopic liver transplantation (OLT) for hepatitis C–associated end-stage liver disease or hepatocellular carcinoma is a vexing clinical problem. Rapid reinfection of the liver graft by hepatitis C virus (HCV) particles in the blood is nearly universal, and the ensuing disease often runs an accelerated course quickly progressing to graft cirrhosis and retransplantation or death.1 In contrast to hepatitis B, no passive immunoprophylaxis is currently available.

90 For practical application, we also developed a simplified mode

90.For practical application, we also developed a simplified model using a single predictor variable Z. When Z1=G1+G2+G6+G8, the AUG was 0.89 and the positive predictive value (PPV) of Z1 > 2 for decompensated cirrhosis was

94%. When C1 and C2 were excluded from the model, the AUG for G6 and G8 alone was 0.75. A third model where Z2=G4+G6+G8+G10 had an AUG of 0.83 and a PPV of 87% for Z2 > 2. Conclusion: Algorithms based on ICD-9 codes related to bleeding esophageal varices and ascites were associated with a high likelihood of identifying CHB and CHC patients with decompensated cirrhosis. This model could constitute a useful tool for epidemiological research and could also be used as a quality improvement measure to electronically prompt timely specialty Proteasome inhibitor referrals and monitor evidence based care of this patient population. Disclosures: Stuart C. Gordon – Advisory Committees or Review Panels: Tibotec; Consulting: Merck, CVS Caremark, Gilead Sciences, BMS; Grant/Research Support: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS, Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc. The following people have nothing to disclose: Wadih Chacra, David Rabin, James J. Yang “
“Estrogens inhibit stellate

cell activation and fibrogenesis. Thus, gender and reproductive states may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). To investigate the association between gender, menopause, and the severity of liver fibrosis in patients with NASH, we analyzed 541 Sirolimus adult patients enrolled from our Duke Liver Clinics (n = 338) and the Duke Metabolic and Weight Loss Surgery Program (n = 203) who had a histologic diagnosis of NASH. Multiple ordinal logistic regression models were used to assess the association between gender, menopause, and severity of liver fibrosis. Overall, men, premenopausal, and postmenopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. The mean age was 48 years and 22% had advanced fibrosis. After adjusting for covariates (enrolling site, grades of portal inflammation, and hepatocyte ballooning) and potential confounders (race, body mass index, diabetes/prediabetes, hypertension),

adjusted cumulative odd ratio (ACOR) and 95% confidence interval (CI) for greater fibrosis BCKDHB severity was 1.4 (0.9, 2.1) (P = 0.17) for postmenopausal women and 1.6 (1.0, 2.5) (P = 0.03) for men, having premenopausal women as a reference. There was borderline interaction between gender and age group divided by age 50, the average age at menopause in the U.S. (P = 0.08): ACOR and 95% CI of having greater fibrosis severity in men compared to women was 1.8 (1.1, 2.9) for patients with age <50 years (P = 0.02) and 1.2 (0.7, 2.1) for patients with age ≥50 years (P = 0.59). Conclusion: Men are at a higher risk of having more severe fibrosis compared to women before menopause, while postmenopausal women have a similar severity of liver fibrosis compared to men.

The most rapidly expanding area in gastrointestinal surgery is ba

The most rapidly expanding area in gastrointestinal surgery is bariatric surgery and the continuing epidemic in obesity and related

type 2 diabetes is likely to ensure that this area will grow further in the future. “
“The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription learn more factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet–fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding

protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element–like elements and one sterol regulatory nearly element (SRE)-binding Sotrastaurin clinical trial site within a −2,468 ∼+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c–induced

Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α–mediated, SREBP-1c–dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. (Hepatology 2013;58:617–628) Nonalcoholic fatty liver disease (NAFLD) is a common component of metabolic syndrome, which has become an epidemic worldwide as a result of improved living conditions, excessive food intake, and sedentary lifestyles. NAFLD comprises a spectrum of liver pathology, including bland steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is estimated to be present in up to 20% of the general population in the United States and ∼15% in China.[1] NAFLD is mostly accompanied by obesity, type 2 diabetes, and dyslipidemia.[2] Although the underlying mechanisms remain unclear, NAFLD is considered to represent a state of fat accumulation, mainly triglycerides (TGs), in hepatocytes, and its pathogenesis is associated with hepatic insulin resistance and enhanced liver lipogenesis.