TY  - JOUR
AU  - Lenz, D.*
AU  - Schlieben, L.D.
AU  - Staufner, C.*
AU  - Prokisch, H.
C1  - 73017
C2  - 56893
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - E106-E107
TI  - Response to "the race against time in genetic testing for PALF".
JO  - Hepatology
VL  - 81
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2025
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - OBJECTIVE: We demonstrated in the randomized 18-month DIRECT PLUS trial (n=294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with two other healthy diets, reducing NAFLD by half, regardless similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention. METHODS: We calculated IHF% by proton-magnetic-resonance-spectroscopy (H-MRS; normal-IHF%<5%; abnormal-IHF%>=5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers. RESULTS: Participants (age=51.3±10.8years; 89%men; body-mass-index=31.3±3.9 kg/m2) had an 89.8% 18-month-retention-rate; 83% had eligible follow-up proteomics-measurements, and 78% had follow-up H-MRS. At baseline, 39-candidate-proteins were significantly associated with IHF% (FDR<0.05), mostly related to immune-function-pathways (e.g., HAOX1). An IHF%-prediction based on the DIRECT PLUS by combined-model (R2=0.47, RMSE=1.05) successfully predicted IHF% (R2=0.53) during testing and was stronger than separately-inputting-proteins/traditional markers (R2=0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39-candidate-proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular-matrix-remodeling, and immune-function pathways. THBS2 protein-change was higher in the green-MED compared to the MED group, beyond weight-and-IHF%-loss (p-value=0.01). Protein principal-component-analysis revealed differences in the 3rd-principal-component time-distinct interactions across abnormal/normal-IHF% trajectory combinations; p<0.05 for all). CONCLUSIONS: Our findings suggest novel proteomic signatures that may indicate MRI-assessed intrahepatic fat state and changes during lifestyle intervention. Specifically, CA5A, HAOX1, and THBS2 protein changes are independently associated with IHF% change, and THBS2 protein change is greater in the green-MED/high-polyphenols diet.
AU  - Goldberg, D.T.*
AU  - Yaskolka Meir, A.*
AU  - Tsaban, G.*
AU  - Rinott, E.*
AU  - Kaplan, A.*
AU  - Zelicha, H.*
AU  - Klöting, N.
AU  - Ceglarek, U.*
AU  - Iserman, B.*
AU  - Shelef, I.*
AU  - Rosen, P.*
AU  - Blüher, M.
AU  - Stumvoll, M.
AU  - Etzion, O.*
AU  - Stampfer, M.J.*
AU  - Hu, F.B.*
AU  - Shai, I.
C1  - 70385
C2  - 55551
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 198-211
TI  - Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes; the DIRECT PLUS clinical trial.
JO  - Hepatology
VL  - 81
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-β is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can modulate TGF-β signaling during liver fibrosis. Expression of the axon guidance molecules semaphorins (SEMAs), which signal through plexins and neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. APPROACH AND RESULTS: We analyzed publicly available patient databases and liver biopsies. We used transgenic mice, in which genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the semaphorin family in liver samples from patients with cirrhosis. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis, or HBV-induced hepatitis discriminates those with a more profibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs on activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained on activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. CONCLUSION: SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.
AU  - De Angelis Rigotti, F.*
AU  - Wiedmann, L.*
AU  - Hubert, M.O.*
AU  - Vacca, M.*
AU  - Hasan, S.S.*
AU  - Moll, I.*
AU  - Carvajal, S.*
AU  - Jiménez, W.*
AU  - Starostecka, M.*
AU  - Billeter, A.T.*
AU  - Müller-Stich, B.*
AU  - Wolff, G.
AU  - Ekim Üstünel, B.
AU  - Herzig, S.
AU  - Fandos-Ramo, C.*
AU  - Krätzner, R.*
AU  - Reich, M.*
AU  - Keitel-Anselmino, V.*
AU  - Heikenwälder, M.*
AU  - Mogler, C.*
AU  - Fischer, A.*
AU  - Rodriguez-Vita, J.*
C1  - 67607
C2  - 53914
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1092-1105
TI  - Semaphorin 3C exacerbates liver fibrosis.
JO  - Hepatology
VL  - 78
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.
AU  - Lenz, D.*
AU  - Schlieben, L.D.
AU  - Shimura, M.
AU  - Bianzano, A.*
AU  - Smirnov, D.
AU  - Kopajtich, R.
AU  - Berutti, R.
AU  - Adam, R.*
AU  - Aldrian, D.*
AU  - Baric, I.*
AU  - Baumann, U.*
AU  - Bozbulut, N.E.*
AU  - Brugger, M.*
AU  - Brunet, T.*
AU  - Bufler, P.*
AU  - Burnyte, B.*
AU  - Calvo, P.L.*
AU  - Crushell, E.*
AU  - Dalgıç, B.*
AU  - Das, A.M.*
AU  - Dezsőfi, A.*
AU  - Distelmaier, F.*
AU  - Fichtner, A.*
AU  - Freisinger, P.*
AU  - Garbade, S.F.*
AU  - Gaspar, H.*
AU  - Goujon, L.*
AU  - Hadzic, N.*
AU  - Hartleif, S.*
AU  - Hegen, B.*
AU  - Hempel, M.*
AU  - Henning, S.*
AU  - Hoerning, A.*
AU  - Houwen, R.*
AU  - Hughes, J.*
AU  - Iorio, R.*
AU  - Iwanicka-Pronicka, K.*
AU  - Jankofsky, M.*
AU  - Junge, N.*
AU  - Kanavaki, I.*
AU  - Kansu, A.*
AU  - Kaspar, S.*
AU  - Kathemann, S.*
AU  - Kelly, D.*
AU  - Kırsaçlıoğlu, C.T.*
AU  - Knoppke, B.*
AU  - Kohl, M.*
AU  - Kölbel, H.*
AU  - Kolker, S.*
AU  - Konstantopoulou, V.*
AU  - Krylova, T.*
AU  - Kuloglu, Z.*
AU  - Kuster, A.*
AU  - Laass, M.W.*
AU  - Lainka, E.*
AU  - Lurz, E.*
AU  - Mandel, H.*
AU  - Mayerhanser, K.*
AU  - Mayr, J.A.*
AU  - McKiernan, P.*
AU  - McLean, P.*
AU  - McLin, V.*
AU  - Mention, K.*
AU  - Müller, H.*
AU  - Pasquier, L.*
AU  - Pavlov, M.
AU  - Pechatnikova, N.*
AU  - Peters, B.*
AU  - Petkovic Ramadža, D.*
AU  - Piekutowska-Abramczuk, D.*
AU  - Pilic, D.*
AU  - Rajwal, S.*
AU  - Rock, N.*
AU  - Roetig, A.*
AU  - Santer, R.*
AU  - Schenk, W.*
AU  - Semenova, N.*
AU  - Sokollik, C.*
AU  - Sturm, E.*
AU  - Taylor, R.W.*
AU  - Tschiedel, E.*
AU  - Urbonas, V.*
AU  - Urreizti, R.*
AU  - Vermehren, J.*
AU  - Vockley, J.*
AU  - Vogel, G.F.*
AU  - Wagner, M.*
AU  - van der Woerd, W.*
AU  - Wortmann, S.*
AU  - Zakharova, E.*
AU  - Hoffmann, G.F.*
AU  - Meitinger, T.*
AU  - Murayama, K.*
AU  - Staufner, C.*
AU  - Prokisch, H.
C1  - 68766
C2  - 54976
SP  - 1075-1087
TI  - Genetic landscape of pediatric acute liver failure of indeterminate origin.
JO  - Hepatology
VL  - 79
IS  - 5
PY  - 2023
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is initiated by steatosis and can progress via fibrosis and cirrhosis to hepatocellular carcinoma (HCC). The RNA binding protein HuR controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte-HuR in NAFLD development and progression to fibrosis and HCC. APPROACH AND RESULTS: Hepatocyte-specific HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or a NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis and HCC development were studied by histology, flow cytometry, quantitative PCR and RNA sequencing. The liver lipidome was characterized by lipidomics analysis and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation-sequencing. Hepatocyte-specific HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition, compared to control HuR-sufficient mice. On a NAFLD-inducing diet, hepatocyte-specific HuR-deficiency resulted in exacerbated inflammation, fibrosis and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics and RNA-immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady-state, a triglyceride signature resembling that of NAFLD livers. Moreover, upregulation of Spp1 and its product osteopontin mediated, at least partially, the fibrosis development in hepatocyte-specific HuR deficiency on a NAFLD-inducing diet, as shown by experiments utilizing antibody blockade of osteopontin. CONCLUSIONS: HuR is a gatekeeper of liver homeostasis preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.
AU  - Subramanian, P.*
AU  - Gargani, S.*
AU  - Palladini, A.
AU  - Chatzimike, M.*
AU  - Grzybek, M.
AU  - Peitzsch, M.*
AU  - Papanastasiou, A.D.*
AU  - Pyrina, I.*
AU  - Ntafis, V.*
AU  - Gercken, B.*
AU  - Lesche, M.*
AU  - Petzold, A.*
AU  - Sinha, A.*
AU  - Nati, M.*
AU  - Thangapandi, V.R.*
AU  - Kourtzelis, I.*
AU  - Andreadou, M.*
AU  - Witt, A.*
AU  - Dahl, A.*
AU  - Burkhardt, R.*
AU  - Haase, R.*
AU  - de Jesus Domingues, A.M.*
AU  - Henry, I.*
AU  - Zamboni, N.*
AU  - Mirtschink, P.*
AU  - Chung, K.J.*
AU  - Hampe, J.*
AU  - Coskun, Ü.
AU  - Kontoyiannis, D.L.*
AU  - Chavakis, T.
C1  - 63057
C2  - 51255
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 881-897
TI  - The RNA binding protein HuR is a gatekeeper of liver homeostasis.
JO  - Hepatology
VL  - 75
IS  - 4
PB  - Wiley
PY  - 2022
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here we investigate the causal effects of risk factors considered in current GBC prevention programmes as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH & RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (p = 9 × 10-5 ) and Europeans (p = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (p = 0.03), while higher CRP concentrations increased GBC risk in Europeans (p = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (p = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean programme for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.
AU  - Barahona Ponce, C.*
AU  - Scherer, D.*
AU  - Brinster, R.*
AU  - Boekstegers, F.*
AU  - Marcelain, K.*
AU  - Gárate, V.*
AU  - Müller, B.*
AU  - de Toro, G.*
AU  - Retamales, J.*
AU  - Barajas, O.*
AU  - Ahumada, M.*
AU  - Morales, E.*
AU  - Rojas, A.*
AU  - Sanhueza, V.*
AU  - Loader, D.*
AU  - Rivera, M.T.*
AU  - Gutiérrez, L.*
AU  - Bernal, G.*
AU  - Ortega, A.*
AU  - Montalvo, D.*
AU  - Portiño, S.*
AU  - Bertrán, M.E.*
AU  - Gabler, F.*
AU  - Spencer, L.*
AU  - Olloquequi, J.*
AU  - Fischer, C.*
AU  - Jenab, M.*
AU  - Aleksandrova, K.*
AU  - Katzke, V.*
AU  - Weiderpass, E.*
AU  - Bonet, C.*
AU  - Moradi, T.*
AU  - Fischer, K.*
AU  - Bossers, W.*
AU  - Brenner, H.*
AU  - Hveem, K.*
AU  - Eklund, N.*
AU  - Völker, U.*
AU  - Waldenberger, M.
AU  - Fuentes Guajardo, M.
AU  - Gonzalez-Jose, R.*
AU  - Bedoya, G.*
AU  - Bortolini, M.C.*
AU  - Canizales, S.*
AU  - Gallo, C.*
AU  - Ruiz Linares, A.*
AU  - Rothhammer, F.
AU  - Lorenzo Bermejo, J.*
C1  - 61236
C2  - 49763
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1783-1796
TI  - Gallstones, body mass index, C-reactive protein and gallbladder cancer—Mendelian randomization analysis of chilean and European genotype data.
JO  - Hepatology
VL  - 73
IS  - 5
PB  - Wiley
PY  - 2021
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low- and middle-income countries and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH: To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of FFPE gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Pre-processed, quality-controlled data from 82 samples (gallstones n=32, low-grade dysplasia n=13, high-grade dysplasia n=9, GBC n=28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). MAIN RESULTS: The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of CpG islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected CDKN2A, MDM2, TP53, and CCND1. Gains in the targetable ERBB2 were detected in 14% of the GBC samples. CONCLUSIONS: Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.
AU  - Brägelmann, J.*
AU  - Barahona Ponce, C.*
AU  - Marcelain, K.*
AU  - Roessler, S.*
AU  - Goeppert, B.*
AU  - Gallegos, I.*
AU  - Colombo, A.*
AU  - Sanhueza, V.*
AU  - Morales, E.*
AU  - Rivera, M.T.*
AU  - de Toro, G.*
AU  - Ortega, A.*
AU  - Müller, B.*
AU  - Gabler, F.*
AU  - Scherer, D.*
AU  - Waldenberger, M.
AU  - Reischl, E.
AU  - Boekstegers, F.*
AU  - Garate-Calderon, V.*
AU  - Umu, S.U.*
AU  - Rounge, T.B.*
AU  - Popanda, O.*
AU  - Lorenzo Bermejo, J.*
C1  - 61235
C2  - 49764
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2293-2310
TI  - Epigenome-wide analysis of methylation changes in the sequence of gallstone disease, dysplasia, and gallbladder cancer.
JO  - Hepatology
VL  - 73
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - New therapeutic strategies against Hepatitis B virus (HBV) focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia inducible factor 1 alpha (HIF1α) stabilisation has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilisation. We addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase APOBEC3B and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV patients (CHB) were analysed by IHC, and in situ hybridization. The effect of HIF1α induction/stabilisation on differentiated HepaRG or mice +/- HBV +/- LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analysed by RT-qPCR, immunoblotting, ChIP, ICC, and mass-spectrometry. Analysing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilisation, strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knock-down was sufficient to rescue the inhibition of A3B-upregulation and -mediated antiviral effects, whereas HIF2α knock-down had no effect. HIF1α stabilisation decreased the level of RelB protein but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner ARNT. In conclusion, inhibiting HIF1α expression or stabilisation represents a novel anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo, and should be considered as a restricting factor in the development of novel immune therapies.
AU  - Riedl, T.*
AU  - Faure-Dupuy, S.*
AU  - Rolland, M.*
AU  - Schuehle, S.*
AU  - Hizir, Z.*
AU  - Calderazzo, S.*
AU  - Zhuang, X.*
AU  - Wettengel, J.M.
AU  - Lopez, M.A.*
AU  - Barnault, R.*
AU  - Mirakaj, V.*
AU  - Prokosch, S.*
AU  - Heide, D.*
AU  - Leuchtenbergeg, C.*
AU  - Schneider, M.*
AU  - Heßling, B.*
AU  - Stottmeier, B.*
AU  - Wessbecher, I.M.*
AU  - Schirmacher, P.*
AU  - McKeating, J.A.*
AU  - Protzer, U.
AU  - Durantel, D.*
AU  - Lucifora, J.*
AU  - Dejardin, E.*
AU  - Heikenwalder, M.*
C1  - 62020
C2  - 50593
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1766-1781
TI  - HIF1α-mediated RelB/APOBEC3B downregulation allows Hepatitis B Virus persistence.
JO  - Hepatology
VL  - 74
IS  - 4
PB  - Wiley
PY  - 2021
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Kosinska, A.
AU  - Kallin, A.*
AU  - Protzer, U.
AU  - Knolle, P.A.*
C1  - 54542
C2  - 45576
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 334A-334A
TI  - Overcoming liver tolerance to clear persistent HBV infection.
JO  - Hepatology
VL  - 68
PB  - Wiley
PY  - 2018
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The liver bears unique immune properties that support both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remain unclear. Here, we dissect the factors determining the outcome of antiviral immunity using recombinant adenoviruses that reflect the hepatropism and hepatrophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar expression of ovalbumin, luciferase, and green fluorescent protein driven by a strong ubiquitous cytomegalovirus (CMV) promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific, transthyretin (TTR) promoter (Ad-TTR-GOL). Using in vivo bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrated that Ad-TTR-GOL infection always persists, whereas Ad-CMV-GOL infection is always cleared, independent of the number of infected hepatocytes. Failure to clear Ad-TTR-GOL infection involved mechanisms acting during initiation as well as execution of antigen-specific immunity. First, hepatocyte-restricted antigen expression led to delayed and curtailed T-cell expansion—10,000-fold after Ad-CMV-GOL versus 150-fold after Ad-TTR-GOL-infection. Second, CD8 T-cells primed toward antigens selectively expressed by hepatocytes showed high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression levels similar to that seen in chronic hepatitis B. Third, Ad-TTR-GOL but not Ad-CMV-GOL-infected hepatocytes escaped being killed by effector T-cells while still inducing high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression, indicating different thresholds of T-cell receptor signaling relevant for triggering effector functions compared with exhaustion. Conclusion: Our study identifies deficits in the generation of CD8 T-cell immunity toward hepatocyte-expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T-cell killing as independent factors promoting viral persistence. This highlights the importance of addressing both the restauration of CD8 T-cell dysfunction and overcoming local hurdles of effector T-cell function to eliminate virus-infected hepatocytes.
AU  - Manske, K.*
AU  - Kallin, N.*
AU  - König, V.*
AU  - Schneider, A.*
AU  - Kurz, S.*
AU  - Bosch, M.*
AU  - Welz, M.*
AU  - Cheng, R.L.*
AU  - Bengsch, B.*
AU  - Steiger, K.*
AU  - Protzer, U.
AU  - Thimme, R.*
AU  - Knolle, P.A.*
AU  - Wohlleber, D.*
C1  - 54446
C2  - 45605
SP  - 2089-2105
TI  - Outcome of antiviral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes.
JO  - Hepatology
VL  - 68
IS  - 8
PY  - 2018
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Michler, T.
AU  - Kosinska, A.
AU  - Grimm, D.*
AU  - Heikenwalder, M.*
AU  - Milstein, S.*
AU  - Sepp-Lorenzino, L.*
AU  - Knolle, P.A.*
AU  - Protzer, U.
C1  - 54541
C2  - 45575
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 49A-50A
TI  - Suppression of hepatitis B virus antigens by RNA interference enables therapeutic vaccination to achieve immune control in high-titer virus carriers.
JO  - Hepatology
VL  - 68
PB  - Wiley
PY  - 2018
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - von Loeffelholz, C.*
AU  - Birkenfeld, A.L.
C1  - 53057
C2  - 44287
SP  - 452-453
TI  - Reply.
JO  - Hepatology
VL  - 67
IS  - 1
PY  - 2018
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Reduced expression of the Indy ('I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane associated citrate transporter expressed highly in the liver, protects mice from high-fat diet and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non-human primates, a two year high fat, high sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription via the IL-6-receptor (IL-6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-Stat3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and non-human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.
AU  - von Loeffelholz, C.*
AU  - Lieske, S.
AU  - Neuschäfer-Rube, F.*
AU  - Willmes, D.M.
AU  - Raschzok, N.*
AU  - Sauer, I.M.*
AU  - König, J.*
AU  - Fromm, M.*
AU  - Horn, P.*
AU  - Chatzigeorgiou, A.
AU  - Pathe-Neuschäfer-Rube, A.*
AU  - Jordan, J.*
AU  - Pfeiffer, A.F.H.*
AU  - Mingrone, G.*
AU  - Bornstein, S.R.
AU  - Ströhle, P.*
AU  - Harms, C.*
AU  - Wunderlich, F.T.*
AU  - Helfand, S.L.*
AU  - Bernier, M.*
AU  - de Cabo, R.*
AU  - Shulman, G.I.*
AU  - Chavakis, T.
AU  - Püschel, G.P.*
AU  - Birkenfeld, A.L.
C1  - 50474
C2  - 42303
CY  - Hoboken
SP  - 616-630
TI  - The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism.
JO  - Hepatology
VL  - 66
IS  - 2
PB  - Wiley
PY  - 2017
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA-bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscured. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication. In the cell culture-based models for HBV infection and the liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 (H4R3me2s) on cccDNAwas a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5-triggered H4R3me2s on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1-based hSWI/SNF chromatin remodeler, which resulted in the downregulation of the binding of RNA Pol II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independent of its methyltransferase activity. Further study revealed that PRMT5 interfered with pre-genomic RNA (pgRNA) encapsidation by preventing its interaction with viral polymerase protein through binding to the RT-RH region of polymerase which is crucial for the polymerase-pgRNA interaction. CONCLUSION:
AU  - Zhang, W.*
AU  - Chen, J.*
AU  - Wu, M.*
AU  - Zhang, X.*
AU  - Zhang, M.*
AU  - Yue, L.*
AU  - Li, Y.*
AU  - Liu, J.*
AU  - Li, B.*
AU  - Shen, F.*
AU  - Wang, Y.*
AU  - Bai, L.*
AU  - Protzer, U.
AU  - Levrero, M.*
AU  - Yuan, Z.*
C1  - 50637
C2  - 42651
CY  - Hoboken
SP  - 398-415
TI  - PRMT5 restricts hepatitis B virus replication via epigenetic repression of cccDNA transcription and interference with pgRNA encapsidation.
JO  - Hepatology
VL  - 66
IS  - 2
PB  - Wiley
PY  - 2017
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The IκB-Kinase (IKK) complex - consisting of the catalytic subunits IKKα and IKKβ as well as the regulatory subunit NEMO - mediates activation of the NF-κB pathway, but previous studies suggested the existence of NF-κB-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell-death is a crucial factor in the progression of liver diseases, and Receptor-Interacting-Kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPC) (IKKα/β(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine if RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry and mutagenesis experiments. These analyses revealed that IKKα and IKKβ - in addition to their known function in NF-κB activation - directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKKα/β-dependent RIPK1-phosphorylation in LPC inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development but promoting biliary cell paucity and lethal cholestasis. CONCLUSIONS: Collectively, these findings show that IKK-complex subunits transmits a previously unrecognized signal through RIPK1, which is fundamental for the long term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer.
AU  - Koppe, C.*
AU  - Verheugd, P.*
AU  - Gautheron, J.*
AU  - Reisinger, F.
AU  - Kreggenwinkel, K.*
AU  - Roderburg, C.*
AU  - Quagliata, L.*
AU  - Terracciano, L.*
AU  - Gassler, N.*
AU  - Tolba, R.H.*
AU  - Boege, Y.*
AU  - Weber, A.*
AU  - Karin, M.*
AU  - Luedde, M.*
AU  - Neumann, U.P.*
AU  - Weiskirchen, R.*
AU  - Tacke, F.*
AU  - Vucur, M.*
AU  - Trautwein, C.*
AU  - Lüscher, B.*
AU  - Preisinger, C.*
AU  - Heikenwälder, M.*
AU  - Luedde, T.*
C1  - 49053
C2  - 41573
CY  - Hoboken
SP  - 1217-1231
TI  - IκB kinaseα/β control biliary homeostasis and hepatocarcinogenesis in mice by phosphorylating the cell-death mediator receptor-interacting protein kinase 1.
JO  - Hepatology
VL  - 64
IS  - 4
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Koppe, C.*
AU  - Gautheron, J.*
AU  - Vucur, M.*
AU  - Roderburg, C.*
AU  - Tacke, F.*
AU  - Trautwein, C.*
AU  - Heikenwälder, M.
AU  - Luedde, T.*
C1  - 49983
C2  - 41952
CY  - Hoboken
SP  - 257A-258A
TI  - A new molecular interaction between IKK alpha/beta and RIPK1 regulates biliary homeostasis and hepatocarcinogenesis.
JO  - Hepatology
VL  - 63
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Li, Y.*
AU  - Xia, Y.
AU  - Han, M.*
AU  - Chen, G.*
AU  - Zhang, D.*
AU  - Thasler, W.E.*
AU  - Protzer, U.
AU  - Ning, Q.*
C1  - 49982
C2  - 41953
CY  - Hoboken
SP  - 921A-921A
TI  - IFN-alpha-mediated Base Excision Repair Pathway Correlates with Antiviral Response Against Hepatitis B Virus Infection.
JO  - Hepatology
VL  - 63
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The majority of hepatocellular carcinoma (HCC) develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or non-alcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT) followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4 ). Also, the impact of DDC-induced chronic liver inflammation was compared between two liver tumor models using a combination of AKT-CAT or AKT-NRAS(G12V) . Treatment with DDC and CCl4 significantly facilitated the adenoma-to-carcinoma conversion and accelerated the growth of AKT-CAT tumors. Furthermore, DDC treatment altered the morphology of AKT-CAT tumors and caused loss of lipid droplets. Transcriptome analysis of AKT-CAT tumors revealed that cellular growth and proliferation was mainly affected by chronic inflammation and caused upregulated of Cxcl16, Galectin-3 and Nedd9 among others. Integration with transcriptome profiles from human HCCs further demonstrated that AKT-CAT tumors generated in the context of chronic liver inflammation showed enrichment of poor prognosis gene sets or decrease of good prognosis gene sets. In contrast, DDC had a more subtle effect on AKT-NRAS(G12V) tumors and primarily enhanced already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT-NRAS(G12V) tumors. CONCLUSION: Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation.
AU  - Matter, M.S.*
AU  - Marquardt, J.U.*
AU  - Andersen, J.B.*
AU  - Quintavalle, C.*
AU  - Korokhov, N.*
AU  - Stauffer, J.K.*
AU  - Kaji, K.*
AU  - Decaens, T.*
AU  - Quagliata, L.*
AU  - Elloumi, F.*
AU  - Hoang, T.*
AU  - Molinolo, A.*
AU  - Conner, E.A.*
AU  - Weber, A.*
AU  - Heikenwälder, M.
AU  - Factor, V.M.*
AU  - Thorgeirsson, S.S.*
C1  - 48013
C2  - 39845
CY  - Hoboken
SP  - 1888-1899
TI  - Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype.
JO  - Hepatology
VL  - 63
IS  - 6
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). Efficient suppression of HBV viremia and necroinflammation as a result of nucleos(t)ide analogue treatment is able to reduce HCC incidence; nevertheless, hepatocarcinogenesis can occur in the absence of active hepatitis, correlating with high HBV surface antigen (HBsAg) levels. NF-κB is a central player in chronic inflammation and HCC development. However, in the absence of severe chronic inflammation, the role of NF-κB signaling in HCC development remains elusive. As a model of hepatocarcinogenesis driven by accumulation of HBV envelope polypeptides, HBsAg transgenic mice, which show no HBV-specific immune response, were crossed to animals with hepatocyte-specific inhibition of canonical NF-κB signaling. We detected prolonged, severe endoplasmic reticulum (ER) stress already at 20 weeks of age in NF-κB-deficient hepatocytes of HBsAg-expressing mice. The unfolded protein response (UPR) regulator BiP/GRP78 was downregulated, ATF6 and eIF2α were activated with subsequent overexpression of CHOP. Notably, immune cell infiltrates and liver transaminases were unchanged. However, due to this increased cellular stress, insufficient hepatocyte proliferation due to G1/S-phase cell cycle arrest with overexpression of p27 and emergence of ductular reactions was detected. This culminated in increased DNA damage already at 20 weeks of age and finally led to 100% HCC incidence due to NF-κB inhibition. CONCLUSION: The role of canonical NF-κB signaling in HCC development depends on the mode of liver damage. In the case of HBsAg-driven hepatocarcinogenesis, NF-κB in hepatocytes acts as a critical tumor suppressor by augmenting the ER stress response. This article is protected by copyright. All rights reserved.
AU  - Sunami, Y.*
AU  - Ringelhan, M.
AU  - Kokai, E.*
AU  - Lu, M.*
AU  - O'Connor, T.
AU  - Lorentzen, A.R.
AU  - Weber, A.*
AU  - Rodewald, A.K.*
AU  - Müllhaupt, B.*
AU  - Terracciano, L.*
AU  - Gul, S.*
AU  - Wissel, S.*
AU  - Leithäuser, F.
AU  - Krappmann, D.*
AU  - Riedl, P.*
AU  - Hartmann, D.*
AU  - Schirmbeck, R.*
AU  - Strnad, P.*
AU  - Hüser, N.*
AU  - Kleeff, J.*
AU  - Friess, H.*
AU  - Schmid, R.M.*
AU  - Geisler, F.*
AU  - Wirth, T.*
AU  - Heikenwälder, M.
C1  - 47936
C2  - 39726
CY  - Hoboken
SP  - 1592-1607
TI  - Canonical NF-κB signaling in hepatocytes acts as a tumor-suppressor in HBV surface antigen-driven HCC by controlling the UPR.
JO  - Hepatology
VL  - 63
IS  - 5
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Sunami, Y.*
AU  - Ringelhan, M.
AU  - Kokai, E.*
AU  - Lu, M.*
AU  - O'Connor, T.
AU  - Lorentzen, A.R.
AU  - Weber, A.*
AU  - Rodewald, A.*
AU  - Müllhaupt, B.*
AU  - Terracciano, L.*
AU  - Gul, S.*
AU  - Wissel, S.*
AU  - Leithäuser, F.*
AU  - Krappmann, D.
AU  - Riedl, P.*
AU  - Hartmann, D.*
AU  - Schirmbeck, R.*
AU  - Strnad, P.*
AU  - Hüser, N.*
AU  - Kleeff, J.*
AU  - Friess, H.*
AU  - Schmid, R.M.*
AU  - Geisler, F.*
AU  - Wirth, T.*
AU  - Heikenwälder, M.
C1  - 49985
C2  - 41950
CY  - Hoboken
SP  - 233A-233A
TI  - Canonical NF-kappa B signaling in hepatocytes acts as a tumor-suppressor in hepatitis B virus surface antigen-driven hepatocellular carcinoma by controlling the unfolded protein response.
JO  - Hepatology
VL  - 63
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Hepatitis B virus (HBV) is a major human pathogen and about one third of the global population will be exposed to the virus in their life time. HBV infects hepatocytes where it replicates its DNA and infection can lead to acute and chronic hepatitis with high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type I IFN production, and this occurs through a pathway dependent on the DNA sensor cGAS and the downstream adaptor protein STING. In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type I IFN in response to foreign DNA or HBV infection and mice lacking STING or cGAS exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possess anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. In conclusion, the lack of a functional innate DNA sensing pathway in hepatocytes hampers efficient innate control of HBV infection. This may explain why HBV has adapted to specifically replicate in hepatocytes, and could contribute to the weak capacity of this cell type to clear HBV infection.
AU  - Thomsen, M.K.*
AU  - Nandakumar, R.*
AU  - Stadler, D.
AU  - Malo, A.
AU  - Valls, R.M.*
AU  - Wang, F.*
AU  - Reinert, L.S.*
AU  - Dagnaes-Hansen, F.*
AU  - Hollensen, A.K.*
AU  - Mikkelsen, J.G.*
AU  - Protzer, U.
AU  - Paludan, S.R.*
C1  - 48834
C2  - 41441
CY  - Hoboken
SP  - 746-759
TI  - Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.
JO  - Hepatology
VL  - 64
IS  - 3
PB  - Wiley-blackwell
PY  - 2016
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Endig, J.*
AU  - Buitrago, L.E.*
AU  - Marhenke, S.*
AU  - Saborowski, A.*
AU  - Schuett, J.*
AU  - Reisinger, F.*
AU  - Limbourg, F.*
AU  - Koenecke, C.*
AU  - Schreder, A.*
AU  - Geffers, R.*
AU  - Manns, M.P.*
AU  - Heikenwälder, M.
AU  - Longerich, T.*
AU  - Vogel, A.*
C1  - 47876
C2  - 39705
SP  - 1244A
TI  - CD8+ T-cells drive liver injury and hepatocellular carcinoma in chronic liver disease.
JO  - Hepatology
VL  - 62
PY  - 2015
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Li, Y.*
AU  - Xia, Y.C.
AU  - Han, M.*
AU  - Chen, G.*
AU  - Thasler, W.E.*
AU  - Luo, X.*
AU  - Protzer, U.
AU  - Ning, Q.*
C1  - 47875
C2  - 39706
SP  - 1030A
TI  - IFN-α-mediated base excision repair pathway correlates with antiviral response against Hepatitis B Virus infection.
JO  - Hepatology
VL  - 62
PY  - 2015
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Due to its ability to inhibit pro-metastatic matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP)-1 has been thought to suppress tumor metastasis. However, elevated systemic levels of TIMP-1 correlate with poor prognosis in cancer patients suggesting a metastasis-stimulating role of TIMP-1. In colorectal cancer patients, tumor as well as plasma TIMP-1 levels were correlated with synchronous liver metastasis or distant metastasis-associated disease relapse. In mice, high systemic TIMP-1 levels increased the liver susceptibility towards metastasis by triggering the formation of a pre-metastatic niche. This promoted hepatic metastasis independent of origin or intrinsic metastatic potential of tumor cells. High systemic TIMP-1 led to increased hepatic SDF-1 levels, which in turn promoted recruitment of neutrophils to the liver. Both inhibition of SDF-1-mediated neutrophil recruitment and systemic depletion of neutrophils reduced TIMP-1-induced increased liver susceptibility towards metastasis. This indicates a crucial functional role of neutrophils in the TIMP-1-induced pre-metastatic niche. Conclusion: Our results identify TIMP-1 as an essential promoter of hepatic pre-metastatic niche formation.
AU  - Seubert, B.*
AU  - Grünwald, B.*
AU  - Kobuch, J.*
AU  - Cui, H.
AU  - Schelter, F.*
AU  - Schaten, S.*
AU  - Siveke, J.T.*
AU  - Lim, N.H.*
AU  - Nagase, H.*
AU  - Simonavicius, N.
AU  - Heikenwälder, M.
AU  - Reinheckel, T.*
AU  - Sleeman, J.P.*
AU  - Janssen, K.P.*
AU  - Knolle, P.A.*
AU  - Krüger, A.*
C1  - 31971
C2  - 34920
SP  - 238-248
TI  - TIMP-1 creates a pre-metastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice.
JO  - Hepatology
VL  - 61
IS  - 1
PY  - 2015
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Gene therapy has become an accepted concept for the treatment of a variety of different diseases. In contrast to pre-clinical models, subjects enrolled in clinical trials including gene therapy possess a history of infection with microbes that may influence its safety and efficacy. Especially viruses that establish chronic infections in the liver, one of the main targets for in vivo gene therapy, raise important concerns. Amongst them is the Hepatitis B virus (HBV), which has chronically infected more than 350 million people worldwide. Here, we investigated the impact of HBV on Adeno-associated viral (AAV) vectors, the most frequently applied gene transfer vehicles for in vivo gene therapy. Unexpectedly we found that HBV greatly improved AAV transduction in cells replicating HBV and identified HBx as a key factor. While HBV-positive and -negative cells were indistinguishable with respect to cell entry efficiency, significantly higher numbers of AAV vector genomes were successfully delivered to the nucleus in the presence of HBV. The HBV-promoting effect was abolished by inhibitors of phosphatidylinositol-3-kinase (PI3K). PI3K was required for efficient trafficking of AAV to the nucleus and was enhanced in HBV-replicating cells and upon HBx expression. Enhancement of AAV transduction was confirmed in vivo using HBV-transgenic mice and could successfully be applied to inhibit HBV progeny release. Conclusion: Our results demonstrate that acute as well as chronic infections with unrelated viruses change the intracellular milieu thereby likely influencing gene therapy outcomes. In case of HBV, the HBx-mediated enhancement of AAV transduction is an advantage that could be exploited for the development of novel treatments of HBV infection.
AU  - Hösel, M.*
AU  - Lucifora, J.
AU  - Michler, T.
AU  - Holz, G.*
AU  - Gruffaz, M.*
AU  - Stahnke, S.*
AU  - Zoulim, F.*
AU  - Durantel, D.*
AU  - Heikenwälder, M.
AU  - Nierhoff, D.*
AU  - Millet, R.*
AU  - Salvetti, A.*
AU  - Protzer, U.
AU  - Buning, H.*
C1  - 29286
C2  - 31525
CY  - Hoboken
SP  - 2110-2120
TI  - Hepatitis B virus infection enhances susceptibility towards adeno-associated viral vector transduction in vitro and in vivo.
JO  - Hepatology
VL  - 59
IS  - 6
PB  - Wiley-Blackwell
PY  - 2014
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.
AU  - Ellinghaus, D.*
AU  - Folseraas, T.*
AU  - Holm, K.*
AU  - Ellinghaus, E.*
AU  - Melum, E.*
AU  - Balschun, T.*
AU  - Laerdahl, J.K.*
AU  - Shiryaev, A.*
AU  - Gotthardt, D.N.*
AU  - Weismüller, T.J.*
AU  - Schramm, C.*
AU  - Wittig, M.*
AU  - Bergquist, A.*
AU  - Björnsson, E.*
AU  - Marschall, H.U.*
AU  - Vatn, M.*
AU  - Teufel, A.*
AU  - Rust, C.*
AU  - Gieger, C.
AU  - Wichmann, H.-E.
AU  - Runz, H.*
AU  - Sterneck, M.*
AU  - Rupp, C.*
AU  - Braun, F.*
AU  - Weersma, R.K.*
AU  - Wijmenga, C.*
AU  - Ponsioen, C.Y.*
AU  - Mathew, C.G.*
AU  - Rutgeerts, P.*
AU  - Vermeire, S.*
AU  - Schrumpf, E.*
AU  - Hov, J.R.*
AU  - Manns, M.P.*
AU  - Boberg, K.M.*
AU  - Schreiber, S.*
AU  - Franke, A.*
AU  - Karlsen, T.H.*
C1  - 26134
C2  - 32086
SP  - 1074-1083
TI  - Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.
JO  - Hepatology
VL  - 58
IS  - 3
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown. By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell-specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification of embryonic hepatoblasts, but alsowhen expressed in up to 6-month-old adult liversrapidly reprograms adult hepatocytes to biliary cells with formation of tubular-cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable of inducing a ductular reaction. Furthermore, we characterized the significance of key effectors of canonical Notch signaling during normal development and in N2IC-expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC-induced specification and morphogenesis of embryonic hepatoblasts and biliary conversion of adult hepatocytes all critically rely on canonical Notch signaling via recombination signal binding protein (RBP)-J but do not require Hes1. Conclusion: Notch2 appears to be the main determinant not only of biliary commitment of embryonic hepatoblasts during development but also of biliary reprogramming of adult hepatocytes. Notch2-dictated cell fates and morphogenesis in both embryonic hepatoblasts and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active.
AU  - Jeliazkova, P.*
AU  - Jors, S.*
AU  - Lee, M.*
AU  - Zimber-Strobl, U.
AU  - Ferrer, J.*
AU  - Schmid, R.M.*
AU  - Siveke, J.T.*
AU  - Geisler, F.*
C1  - 25980
C2  - 32039
SP  - 2469-2479
TI  - Canonical notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1.
JO  - Hepatology
VL  - 57
IS  - 6
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - BACKGROUND: Alternatively polarized macrophages (MΦ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anti-cancer immune responses. We investigated if Sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed NK cell responses. METHODS: In vivo experiments were conducted with Sorafenib (25 mg/kg) treated C57BL/6 wild-type as well as HBV and lymphotoxin transgenic mice with and without HCC. Monocyte derived MΦ or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with Sorafenib (0.07-5.0 µg/ml) and co-cultured with autologous NK cells. MΦ and NK cell activation was analyzed by flow cytometry and killing assays, respectively. Cytokine and growth factor release was measured by ELISA. RESULTS: Short-term administration of Sorafenib triggered activation of hepatic NK cells in wild-type and tumor bearing mice. In vitro, Sorafenib sensitized MΦ to LPS reverting alternative MΦ polarization and enhanced IL12 secretion (P=0.0133). NK cells activated by Sorafenib-treated MΦ showed increased degranulation (15.3±0.2% vs. 32.0±0.9%, P<0.0001) and IFNγ secretion (2.1±0.2% vs. 8.0±0.2%, P<0.0001) upon target cell contact. Sorafenib-triggered NK cell activation was verified by co-culture experiments using TAM. Sorafenib-treated MΦ increased cytolytic NK cell function against K562, Raji and HepG2 target cells in a dose-dependent manner. Neutralization of IL12 or IL18 as well as inhibition of the NFκB pathway reversed NK cell activation in MΦ/NK co-cultures. CONCLUSION: Sorafenib triggers pro-inflammatory activity of TAM and subsequently induces anti-tumoral NK cell responses in a cytokine and NFĸB-dependent fashion. This observation is relevant for HCC therapy, as Sorafenib is a compound in clinical use, which reverses alternative polarization of TAM in HCC.
AU  - Sprinzl, M.F.
AU  - Reisinger, F.
AU  - Puschnik, A.
AU  - Ringelhan, M.
AU  - Ackermann, K.
AU  - Hartmann, D.*
AU  - Schiemann, M.
AU  - Weinmann, A.*
AU  - Galle, P.R.*
AU  - Schuchmann, M.*
AU  - Friess, H.*
AU  - Otto, G.*
AU  - Heikenwälder, M.
AU  - Protzer, U.
C1  - 23817
C2  - 31290
SP  - 2358-2368
TI  - Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cells.
JO  - Hepatology
VL  - 57
IS  - 6
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0270-9139
ER  - 

TY  - JOUR
AU  - Xia, Y.
AU  - Lucifora, J.
AU  - Zhang, K.
AU  - Cheng, X.
AU  - Stadler, D.
AU  - Reisinger, F.
AU  - Feuerherd, M.
AU  - Makowska, Z.*
AU  - Hartmann, D.*
AU  - Thasler, W.E.*
AU  - Heim, M.H.*
AU  - Heikenwälder, M.
AU  - Protzer, U.
C1  - 30750
C2  - 33865
CY  - Hoboken
SP  - 274A-275A
TI  - Interferons induce degradation of HBV CccDNA.
JO  - Hepatology
VL  - 58
PB  - Wiley-blackwell
PY  - 2013
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Adeno-associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic
AU  - Hösel, M.*
AU  - Broxtermann, M.
AU  - Janicki, H.*
AU  - Esser, K.
AU  - Arzberger, S.
AU  - Hartmann, P.*
AU  - Gillen, S.*
AU  - Kleeff, J.*
AU  - Stabenow, D.*
AU  - Odenthal, M.*
AU  - Knolle, P.*
AU  - Hallek, M.*
AU  - Protzer, U.
AU  - Buning, H.*
C1  - 8045
C2  - 29950
SP  - 287-297
TI  - Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors.
JO  - Hepatology
VL  - 55
IS  - 1
PB  - Wiley-Blackwell
PY  - 2012
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4+ Foxp3+ regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. Conclusion: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. (HEPATOLOGY 2012;56:873883)
AU  - Stross, L.
AU  - Günther, J.
AU  - Gasteiger, G.
AU  - Asen, T.
AU  - Graf, S.
AU  - Aichler, M.
AU  - Esposito, I.
AU  - Busch, D.H.
AU  - Knolle, P.*
AU  - Sparwasser, T.*
AU  - Protzer, U.
C1  - 8626
C2  - 30262
SP  - 873-883
TI  - Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice.
JO  - Hepatology
VL  - 56
IS  - 3
PB  - Wiley-Blackwell
PY  - 2012
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - In vivo evaluation of CD8 T cell effector (cytotoxic T lymphocyte [CTL]) function in peripheral organs such as the liver is currently not possible but would greatly improve our understanding of local immune regulation, because simple determination of antigen-specific CTL numbers does not predict the outcome of immune responses. In particular, measurement of alanine aminotransferase serum levels is not sensitive enough to detect T cell immunity against low numbers of target hepatocytes. We developed a procedure that detects virus-specific effector function of CTLs in the liver after simultaneous adenoviral transfer of reporter and immune target genes into hepatocytes, followed by bioluminescence imaging of reporter genes. Bioluminescence imaging enabled detection of as few as 10,000 infected hepatocytes in vivo, and even more importantly, quantification of antiviral effector function of as few as 50,000 CTLs. Conclusion: Our results provide evidence that low numbers of antigen-specific CTLs are sufficient to control viral gene expression and eliminate viral infection from hepatocytes. The experimental system established here is a highly sensitive method to simultaneously detect viral infection of hepatocytes and to quantify antiviral CTL function in the liver in vivo and will help in characterizing principles of hepatic immune regulation.
AU  - Stabenow, D.*
AU  - Frings, M.*
AU  - Trück, C.*
AU  - Gärtner, K.*
AU  - Förster, I.*
AU  - Kurts, C.*
AU  - Tüting, T.*
AU  - Odenthal, M.*
AU  - Dienes, H.P.*
AU  - Cederbrant, K.*
AU  - Protzer, U.
AU  - Knolle, P.A.*
C1  - 5575
C2  - 27774
SP  - 1430-1437
TI  - Bioluminescence imaging allows measuring CD8 T cell function in the liver.
JO  - Hepatology
VL  - 51
IS  - 4
PB  - Wiley-Blackwell
PY  - 2010
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The aim of the present study was to investigate the association of serum gamma-glutamyltransferase (GGT) levels with all-cause mortality and to assess the impact of ultrasonographic findings of hepatic hyperechogenicity in that association. We used data from 4,160 subjects (2,044 men and 2,116 women) recruited for the population-based Study of Health in Pomerania (SHIP) without baseline hepatitis B and C infections or liver cirrhosis. GGT was divided into age- and sex-dependent quintiles to calculate overall and sex-specific crude incidence mortality rates. Hepatic steatosis was defined by elevated GGT levels (>80%) and the presence of hyperechogenic liver ultrasound. We used multiple-adjusted Cox proportional hazards regression models, first, to assess the direct effect of GGT on all-cause mortality, second, to stratify according to the ultrasonographic finding, and third, to investigate potential mediating effects of cardiometabolic risk factors. During 29,810 person-years (7.3 years, median) of follow-up, 307 individuals (7.5%) died, resulting in a death rate of 0.86 deaths per 1000 person-years. Elevated GGT levels were associated with increased risk of mortality in men (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.08-2.05), but not in women (HR 1.30; 95% CI, 0.80-2.12). This association was even stronger in men with hepatic steatosis (HR 1.98; 95% CI, 1.21-3.27). Cause-specific mortality analysis by cardiovascular disease deaths confirmed the sex-specific association. Adjustment for cardiometabolic risk factors did not affect the estimates. CONCLUSION: In the case of increased GGT levels, liver ultrasound should be performed, not only for diagnosis, but also for further risk stratification.
AU  - Haring, R.*
AU  - Wallaschofski, H.*
AU  - Nauck, M.*
AU  - Dörr, M.*
AU  - Baumeister, S.E.
AU  - Völzke, H.*
C1  - 496
C2  - 27050
SP  - 1403-1411
TI  - Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.
JO  - Hepatology
VL  - 50
IS  - 5
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - With about 350 million virus carriers, hepatitis B virus (HBV) infection remains a major health problem. HBV is a noncytopathic virus causing persistent infection, but it is still unknown whether host recognition of HBV may activate an innate immune response. We describe that upon infection of primary human liver cells, HBV is recognized by nonparenchymal cells of the liver, mainly by liver macrophages (Kupffer cells), although they are not infected. Within 3 hours, this recognition leads to the activation of nuclear factor kappa B (NF-kappaB) and subsequently to the release of interleukin-6 (IL-6) and other proinflammatory cytokines (IL-8, TNF-alpha, IL-1beta), but does not induce an interferon response. The activation of proinflammatory cytokines, however, is transient, and even inhibits responsiveness toward a subsequent challenge. IL-6 released by Kupffer cells after activation of NF-kappaB controls HBV gene expression and replication in hepatocytes at the level of transcription shortly after infection. Upon binding to its receptor complex, IL-6 activates the mitogen-activated protein kinases exogenous signal-regulated kinase 1/2, and c-jun N-terminal kinase, which inhibit expression of hepatocyte nuclear factor (HNF) 1alpha and HNF 4alpha, two transcription factors essential for HBV gene expression and replication. CONCLUSION: Our results demonstrate recognition of HBV patterns by nonparenchymal liver cells, which results in IL-6-mediated control of HBV infection at the transcriptional level. Thus, IL-6 ensures early control of the virus, limiting activation of the adaptive immune response and preventing death of the HBV-infected hepatocyte. This pattern recognition may be essential for a virus, which infects a new host with only a few virions. Our data also indicate that therapeutic neutralization of IL-6 for treatment of certain diseases may represent a risk if the patient is HBV-infected.
AU  - Hösel, M.*
AU  - Quasdorff, M.*
AU  - Wiegmann, K.*
AU  - Webb, D.*
AU  - Zedler, U.*
AU  - Broxtermann, M.
AU  - Tedjokusumo, R.
AU  - Esser, K.
AU  - Arzberger, S.
AU  - Kirschning, C.J.*
AU  - Langenkamp, A.*
AU  - Falk, C.*
AU  - Buning, H.*
AU  - Rose-John, S.*
AU  - Protzer, U.
C1  - 358
C2  - 26832
SP  - 1773-1782
TI  - Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection.
JO  - Hepatology
VL  - 50
IS  - 6
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Farnesoid X receptor (FXR/Fxr) is a bile acid-regulated nuclear receptor that promotes hepatic bile acid metabolism, detoxification, and liver regeneration. However, the adaptive pathways under conditions of bile acid stress are not fully elucidated. We found that wild-type but not Fxr knockout mice on diets enriched with chenodeoxycholic acid (CDCA) increase their liver/body weight ratios by 50% due to hepatocellular hypertrophy. Microarray analysis identified Hex (Hematopoietically expressed homeobox), a central transcription factor in vertebrate embryogenesis and liver development, as a novel CDCA- and Fxr-regulated gene. HEX/Hex was also regulated by FXR/Fxr and CDCA in primary mouse hepatocytes and human HepG2 cells. Comparative genomic analysis identified a conserved inverted repeat-1-like DNA sequence within a 300 base pair enhancer element of intron-1 in the human and mouse HEX/Hex gene. A combination of chromatin immunoprecipitation, electromobility shift assay, and transcriptional reporter assays demonstrated that FXR/Fxr binds to this element and mediates HEX/Hex transcriptional activation. CONCLUSION: HEX/Hex is a novel bile acid-induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure.
AU  - Xing, X.*
AU  - Burgermeister, E.*
AU  - Geisler, F.*
AU  - Einwächter, H.*
AU  - Fan, L.*
AU  - Hiber, M.*
AU  - Rauser, S.
AU  - Walch, A.K.
AU  - Röcken, C.*
AU  - Ebeling, M.*
AU  - Wright, M.B.*
AU  - Schmid, R.M.*
AU  - Ebert, M.P.*
C1  - 508
C2  - 25969
SP  - 979-988
TI  - Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy.
JO  - Hepatology
VL  - 49
IS  - 3
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - The Notch pathway is an evolutionary conserved, intercellular signaling pathway that plays an important role in cell fate specification and the embryonic development of many organs, including the liver. In humans, mutations in the Notch receptor ligand Jagged1 gene result in defective intrahepatic bile duct (IHBD) development in Alagille syndrome. Developmental abnormalities of IHBD in mice doubly heterozygous for Jagged1 and Notch2 mutations propose that interactions of Jagged1 and its receptor Notch2 are crucial for normal IHBD development. Because different cell types in the liver are involved in IHBD development and morphogenesis, the cell-specific role of Notch signaling is not entirely understood. We investigated the effect of combined or single targeted disruption of Notch1 and Notch2 specifically in hepatoblasts and hepatoblast-derived lineage cells on liver development using AlbCre transgenic mice. Hepatocyte differentiation and homeostasis were not impaired in mice after combined deletion of Notch1 and Notch2 (N1N2(F/F)AlbCre). However, we detected irregular ductal plate structures in N1N2(F/F)AlbCre newborns, and further postnatal development of IHBD was severely impaired characterized by disorganized ductular structures accompanied by portal inflammation, portal fibrosis, and foci of hepatocyte feathery degeneration in adulthood. Further characterization of mutant mice with single deletion of Notch1 (N1(F/F)AlbCre) or Notch2 (N2(F/F)AlbCre) showed that Notch2 but not Notch1 is indispensable for normal perinatal and postnatal IHBD development. Further reduction of Notch2 gene dosage in Notch2 conditional/mutant (N2(F/LacZ)AlbCre) animals further enhanced IHBD abnormalities and concomitant liver pathology. CONCLUSION: Notch2 is required for proper IHBD development and morphogenesis.
AU  - Geisler, F.*
AU  - Nagl, F.*
AU  - Mazur, P.K.*
AU  - Lee, M.
AU  - Zimber-Strobl, U.
AU  - Strobl, L.J.
AU  - Radtke, F.*
AU  - Schmid, R.M.
AU  - Siveke, J.T.*
C1  - 2421
C2  - 25446
SP  - 607-616
TI  - Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice.
JO  - Hepatology
VL  - 48
IS  - 2
PB  - Wiley-Blackwell
PY  - 2008
SN  - 0270-9139
ER  - 

TY  - JOUR
AB  - Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. CONCLUSION: Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history.
AU  - Rollier, C.S.*
AU  - Paranhos-Baccala, G.*
AU  - Verschoor, E.J.*
AU  - Verstrepen, B.E.*
AU  - Drexhage, J.A.*
AU  - Fagrouch, Z.*
AU  - Berland, J.L.*
AU  - Komurian-Pradel, F.*
AU  - Duverger, B.*
AU  - Himoudi, N.*
AU  - Staib, C.
AU  - Meyr, M.
AU  - Whelan, M.*
AU  - Whelan, J.A.*
AU  - Adams, V.C.*
AU  - Larrea, E.*
AU  - Riezu, J.I.*
AU  - Lasarte, J.J.*
AU  - Bartosch, B.*
AU  - Cosset, F.L.*
AU  - Spaan, W.J.*
AU  - Diepolder, H.M.*
AU  - Pape, G.R.*
AU  - Sutter, G.*
AU  - Inchauspe, G.*
AU  - Heeney, J.L.*
C1  - 1768
C2  - 25353
SP  - 602-613
TI  - Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity.
JO  - Hepatology
VL  - 45
IS  - 3
PB  - Wiley-Blackwell
PY  - 2007
SN  - 0270-9139
ER  -