TY  - JOUR
AB  - BACKGROUND & AIMS: Oxidative stress and antioxidant defense mechanisms have long been implicated in the pathogenesis of acute pancreatitis (AP). However, there is a notable lack of in vivo experimental evidence clarifying their precise role. METHODS: We generated and analyzed mice with a pancreas-specific deletion of Txnrd1 (Txnrd1Δpanc). AP was induced in these mice using caerulein injections. Pancreatic tissue was subsequently analyzed using immunoblotting, histology, immunohistochemistry, RNA sequencing and biochemical assays. RESULTS: Txnrd1Δpanc mice exhibited normal growth, pancreatic weight, histology, and pancreatic function comparable to controls, though they experienced a slightly more severe course of AP. An increase in glutathione levels and upregulation of components within the glutathione system were observed in these mice. However, depletion of the glutathione pool led to pancreatic necrosis, followed by regeneration. When glutathione depletion was combined with AP, Txnrd1Δpanc mice suffered a profound and permanent loss of acinar tissue. CONCLUSIONS: These findings indicate that the response to AP is closely linked to alterations in antioxidant systems. The thioredoxin and the glutathione systems appear to perform overlapping protective roles in safeguarding acinar cells during AP. A simultaneous disruption of both systems proves detrimental to pancreatic integrity during acute pancreatitis.
AU  - Einwächter, H.*
AU  - Li, B.*
AU  - Aichler, M.
AU  - Rickmann, M.*
AU  - Chhabra, N.*
AU  - Oellinger, R.*
AU  - Brielmeier, M.
AU  - Schmid, R.M.*
C1  - 75467
C2  - 58369
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - A redundant system of thioredoxin and glutathione is essential for pancreatic acinar integrity.
JO  - Cell. Mol. Gast. Hept.
VL  - 19
IS  - 12
PB  - Elsevier Inc
PY  - 2025
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a rapidly growing malignancy with high mortality. Recently, metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major HCC catalyst; however, signals driving transition of MASH to HCC remain elusive and treatment options are limited. Herein, we investigated the role of STE20-type kinase STK25, a critical regulator of hepatocellular lipotoxic milieu and MASH susceptibility, in the initiation and progression of MASH-related HCC. METHODS: The clinical relevance of STK25 in HCC was assessed in publicly available datasets and by RT-qPCR and proximity ligation assay in a validation cohort. The functional significance of STK25 silencing in human hepatoma cells was evaluated in vitro and in a subcutaneous xenograft mouse model. The therapeutic potential of STK25 antagonism was examined in a mouse model of MASH-driven HCC, induced by a single diethylnitrosamine injection combined with a high-fat diet. RESULTS: Analysis of public databases and in-house cohorts revealed that STK25 expression in human liver biopsies positively correlated with HCC incidence and severity. The in vitro silencing of STK25 in human hepatoma cells suppressed proliferation, migration, and invasion with efficacy comparable to that achieved by anti-HCC drugs sorafenib or regorafenib. STK25 knockout in human hepatoma cells also blocked tumor formation and growth in a subcutaneous xenograft mouse model. Furthermore, pharmacologic inhibition of STK25 with antisense oligonucleotides-administered systemically or hepatocyte-specifically-efficiently mitigated the development and exacerbation of hepatocarcinogenesis in a mouse model of MASH-driven HCC. CONCLUSION: This study underscores STK25 antagonism as a promising therapeutic strategy for the prevention and treatment of HCC in the context of MASH.
AU  - Xia, Y.*
AU  - Caputo, M.*
AU  - Andersson, E.*
AU  - Asiedu, B.*
AU  - Zhang, J.*
AU  - Hou, W.*
AU  - Amrutkar, M.*
AU  - Cansby, E.*
AU  - Gul, N.*
AU  - Gemmink, A.*
AU  - Myers, C.E.*
AU  - Aghajan, M.*
AU  - Booten, S.L.*
AU  - Hoy, A.J.*
AU  - Härtlova, A.*
AU  - Lindahl, P.*
AU  - Ståhlberg, A.*
AU  - Schaart, G.*
AU  - Hesselink, M.K.C.*
AU  - Peter, A.
AU  - Murray, S.A.*
AU  - Mahlapuu, M.*
C1  - 73576
C2  - 57111
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Therapeutic potential of STE20-type kinase STK25 inhibition for the prevention and treatment of metabolically induced hepatocellular carcinoma.
JO  - Cell. Mol. Gast. Hept.
VL  - 19
IS  - 7
PB  - Elsevier Inc
PY  - 2025
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV uses a physiological liver-directed pathway that supports specific host-cell targeting in vivo. METHODS: We established the ex vivo perfusion of intact human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation. RESULTS: HBV was rapidly sequestered by liver macrophages within 1 hour after a virus pulse perfusion but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins in serum and within machrophages. Electron and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilize the hepatocyte-directed cholesterol transport machinery of macrophages. CONCLUSIONS: Our results propose that by binding to liver targeted lipoproteins and using the reverse cholesterol transport pathway of macrophages, HBV hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve transinfection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes.
AU  - Esser, K.
AU  - Cheng, X.
AU  - Wettengel, J.M.
AU  - Lucifora, J.*
AU  - Hansen-Palmus, L.
AU  - Austen, K.
AU  - Roca Suarez, A.A.*
AU  - Heintz, S.*
AU  - Testoni, B.*
AU  - Nebioglu, F.*
AU  - Pham, M.T.*
AU  - Yang, S.*
AU  - Zernecke, A.*
AU  - Wohlleber, D.*
AU  - Ringelhan, M.*
AU  - Broxtermann, M.
AU  - Hartmann, D.*
AU  - Hüser, N.*
AU  - Mergner, J.*
AU  - Pichlmair, A.
AU  - Thasler, W.E.*
AU  - Heikenwälder, M.
AU  - Gasteiger, G.
AU  - Blutke, A.
AU  - Walch, A.K.
AU  - Knolle, P.A.*
AU  - Bartenschlager, R.*
AU  - Protzer, U.
C1  - 67608
C2  - 53915
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 201-221
TI  - Hepatitis B virus targets lipid transport pathways to infect hepatocytes.
JO  - Cell. Mol. Gast. Hept.
VL  - 16
IS  - 2
PB  - Elsevier Inc
PY  - 2023
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/p53/p21-pathway in a murine model of metabolic liver injury. METHODS: NTBC was reduced or withdrawn in Fah-/- mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas-antibody Jo2. RESULTS: In a model of metabolic liver injury, loss of p53, but not of Chk2, impairs the oxidative stress response and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, revealing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the distinct phenotypes associated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on proliferation and the anti-oxidative stress response. CONCLUSION: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, is related to the level at which the cascade is interrupted.
AU  - Buitrago-Molina, L.E.*
AU  - Marhenke, S.*
AU  - Becker, D.*
AU  - Geffers, R.*
AU  - Itzel, T.*
AU  - Teufel, A.*
AU  - Jaeschke, H.*
AU  - Lechel, A.*
AU  - Unger, K.
AU  - Markovic, J.*
AU  - Sharma, A.D.*
AU  - Marquardt, J.U.*
AU  - Saborowski, M.*
AU  - Saborowski, A.*
AU  - Vogel, A.*
C1  - 61060
C2  - 50024
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 1387-1404
TI  - p53-independent induction of p21 fails to control regeneration and hepatocarcinogenesis in a murine liver injury model.
JO  - Cell. Mol. Gast. Hept.
VL  - 11
IS  - 5
PB  - Elsevier Inc
PY  - 2021
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: RING finger protein 43 (RNF43) is a tumor suppressor that frequently is mutated in gastric tumors. The link between RNF43 and modulation of WNT signaling has not been shown clearly in the stomach. Because mutations in RNF43 are highly enriched in microsatellite-unstable gastric tumors, which show defects in DNA damage response (DDR), we investigated whether RNF43 is involved in DDR in the stomach. METHODS: DDR activation and cell viability upon γ-radiation was analyzed in gastric cells where expression of RNF43 was depleted. Response to chemotherapeutic agents 5-fluorouracil and cisplatin was analyzed in gastric cancer cell lines and xenograft tumors. In addition, involvement of RNF43 in DDR activation was analyzed upon Helicobacter pylori infection in wild-type and Rnf43ΔEx8 mice. Furthermore, a cohort of human gastric biopsy specimens was analyzed for RNF43 expression and mutation status as well as for activation of DDR. RESULTS: RNF43 depletion conferred resistance to γ-radiation and chemotherapy by dampening the activation of DDR, thereby preventing apoptosis in gastric cells. Upon Helicobacter pylori infection, RNF43 loss of function reduced activation of DDR and apoptosis. Furthermore, RNF43 expression correlated with DDR activation in human gastric biopsy specimens, and RNF43 mutations found in gastric tumors conferred resistance to DNA damage. When exploring the molecular mechanisms behind, a direct interaction between RNF43 and γH2AX was observed. CONCLUSIONS: We identified a novel function for RNF43 in the stomach as a regulator of DDR. Loss of RNF43 function in gastric cells confers resistance to DNA damage-inducing radiotherapy and chemotherapy, suggesting RNF43 as a possible biomarker for therapy selection.
AU  - Neumeyer, V.*
AU  - Brutau-Abia, A.*
AU  - Allgäuer, M.*
AU  - Pfarr, N.*
AU  - Weichert, W.*
AU  - Falkeis-Veits, C.*
AU  - Kremmer, E.
AU  - Vieth, M.*
AU  - Gerhard, M.*
AU  - Mejías-Luque, R.*
C1  - 61230
C2  - 49673
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 1071-1094
TI  - Loss of RNF43 function contributes to gastric carcinogenesis by impairing DNA damage response.
JO  - Cell. Mol. Gast. Hept.
VL  - 11
IS  - 4
PB  - Elsevier Inc
PY  - 2021
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - BACKGROUND & AIMS: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.METHODS: Control Atp7b(+/-) and Wilson disease Atp7b(-/-) rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b(-/-) rats to test for therapeutic reversal of mitochondrial copper damage.RESULTS: In comparison with a normal diet, HCD feeding of Atp7b(-/-) rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b(-/-) rats, correlating with severe liver injury. Mitochondria presentedwith massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage.CONCLUSIONS: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
AU  - Einer, C.
AU  - Leitzinger, C.
AU  - Lichtmannegger, J.
AU  - Eberhagen, C.
AU  - Rieder, T.*
AU  - Borchard, S.
AU  - Wimmer, R.*
AU  - Denk, G.*
AU  - Popper, B.*
AU  - Neff, F.
AU  - Polishchuk, E.V.*
AU  - Polishchuk, R.S.*
AU  - Hauck, S.M.
AU  - von Toerne, C.
AU  - Müller, J.C.*
AU  - Karst, U.*
AU  - Baral, B.S.*
AU  - DiSpirito, A.A.*
AU  - Kremer, A.E.*
AU  - Semrau, J.*
AU  - Weiss, K.H.*
AU  - Hohenester, S.*
AU  - Zischka, H.
C1  - 55053
C2  - 46047
CY  - 525 B Street, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 571-596
TI  - A high caloric diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.
JO  - Cell. Mol. Gast. Hept.
VL  - 7
IS  - 3
PB  - Elsevier Inc
PY  - 2019
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.
AU  - Jian, Z.*
AU  - Cheng, T.*
AU  - Zhang, Z.*
AU  - Raulefs, S.*
AU  - Shi, K.*
AU  - Steiger, K.*
AU  - Maeritz, N.*
AU  - Kleigrewe, K.*
AU  - Hofmann, T.*
AU  - Benitz, S.*
AU  - Bruns, P.*
AU  - Lamp, D.
AU  - Jastroch, M.
AU  - Akkan, J.*
AU  - Jäger, C.*
AU  - Huang, P.L.*
AU  - Nie, S.*
AU  - Shen, S.S.*
AU  - Zou, X.*
AU  - Ceyhan, G.O.*
AU  - Michalski, C.W.*
AU  - Friess, H.*
AU  - Kleeff, J.*
AU  - Kong, B.*
C1  - 54437
C2  - 45573
SP  - 429-449
TI  - Glycemic variability promotes both local invasion and metastatic colonization by pancreatic ductal adenocarcinoma.
JO  - Cell. Mol. Gast. Hept.
VL  - 6
IS  - 4
PY  - 2018
SN  - 2352-345X
ER  - 

TY  - JOUR
AB  - Background & Aims The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma (HCC), but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. Methods We performed gene expression profiling of primary human hepatocytes (PHH) infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real time PCR and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and siRNA-mediated knockdown of STAT3. Results Gene expression profiling of HBV-infected PHH detected no interferon response, while genes encoding for acute phase and anti-apoptotic proteins were up-regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV-related HCC. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6-dependent and -independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as siRNA-mediated knockdown of STAT3 induced apoptosis and reduced HBV replication and gene expression. Conclusions HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis.  
AU  - Hösel, M.*
AU  - Quasdorff, M.*
AU  - Ringelhan, M.
AU  - Kashkar, H.*
AU  - Debey-Pascher, S.*
AU  - Sprinzl, M.F.
AU  - Bockmann, J.H.
AU  - Arzberger, S.
AU  - Webb, D.*
AU  - von Olshausen, G.*
AU  - Weber, A.*
AU  - Schultze, J.L.*
AU  - Büning, H.*
AU  - Heikenwälder, M.
AU  - Protzer, U.
C1  - 51568
C2  - 43212
SP  - 339-363
TI  - Hepatitis B virus activates signal transducer and activator of transcription 3 supporting hepatocyte survival and virus replication.
JO  - Cell. Mol. Gast. Hept.
VL  - 4
IS  - 3
PY  - 2017
SN  - 2352-345X
ER  -