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Papers by Peter Fickert

Gastroenterology, 2000

of the N-terminus into the lumen of the ER. This p7-independent membrane association occurred onl... more of the N-terminus into the lumen of the ER. This p7-independent membrane association occurred only co-translationally, indicating the presence of one or more internal signal sequences within NS2. Deletion-mapping analysis of the carboxy-terminal sequence of NS2 indicated that the sequence downstream of amino acid 883 was not required for the membrane association of NS2. However, further deletion of the sequence downstream of amino acid 839 abolished this membrane association. This result indicated that the NS2 sequence located between amino acids 839 and 883 contained a signal sequence to target NS2 to the membrane. Interestingly, the deletion of the amino-terminal sequence upstream of amino acid 884 did not prevent NS2 from becoming membrane-associated. This result indicated that there was another signal sequence located downstream of amino acid 884. Thus the membrane-association of NS2 involves p7 and at least two other internal signal sequences. Taken together, these results indicate that NS2 likely contains multiple membrane-spanning domains.

Zeitschrift für Gastroenterologie, 2015

The Journal of Pathology, 2015

Keratins (K) are cytoprotective proteins and keratin mutations predispose to development of multi... more Keratins (K) are cytoprotective proteins and keratin mutations predispose to development of multiple human diseases. K19 represents the most widely used marker of biliary and hepatic progenitor cells as well as marker of ductular reaction that constitutes the basic regenerative response to chronic liver injury. In the present study, we investigated the role of K19 in biliary and hepatic progenitor cells and its importance for ductular reaction. K19 wild-type (WT) and knockout (KO) mice were fed (i) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC); (ii) cholic acid (CA); (iii) choline-deficient, ethionine-supplemented (CDE) diet; or (iv) were subjected to common bile duct ligation (CBDL). The bile composition, liver damage, bile duct proliferation, oval cell content and biliary fibrosis were analyzed. In untreated animals, loss of K19 led to re-distribution of the K network in biliary epithelial cells (BECs), but to no obvious biliary phenotype. After DDC feeding, K19-KO mice exhibited (compared to WTs) (i) increased cholestasis; (ii) less pronounced ductular reaction with reduced ductular proliferation and fewer oval cells; (iii) impaired Notch 2 signalling in BECs; (iv) lower biliary fibrosis score and biliary bicarbonate concentration. An attenuated oval cell proliferation in K19-KOs was also found after feeding with CDE diet. K19 KOs subjected to CBDL displayed lower BEC proliferation, oval cell content and less prominent Notch 2 signal. K19 deficiency did not change the extent of CA- or CBDL-induced liver injury and fibrosis. Our results demonstrate that K19 plays an important role in ductular reaction and might be of importance to multiple chronic liver disorders that frequently display ductular reaction.

Gastroenterology, 2010

Background: Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and i... more Background: Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-B. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells.

Digestive diseases (Basel, Switzerland), 2015

Kidney injury in deeply jaundiced patients became known as cholemic nephropathy. This umbrella te... more Kidney injury in deeply jaundiced patients became known as cholemic nephropathy. This umbrella term covers impaired renal function in cholestatic patients with characteristic histomorphological changes including intratubular cast formation and tubular epithelial cell injury. Cholemic nephropathy represents a widely underestimated but important cause of kidney dysfunction in patients with cholestasis and advanced liver disease. However, the nomenclature is inconsistent since there are numerous synonyms used; the underlying mechanisms of cholemic nephropathy are not entirely clear, and widely accepted diagnostic criteria are still missing. Consequently, the current article aims to summarize the present knowledge on the clinical and morphological characteristics, available preclinical models, derived potential pathomechanisms, and future diagnostic and therapeutic strategies in cholemic nephropathy. Furthermore, we provide a potential research agenda for this evolving field. © 2015 S. ...

Digestion, 2014

Drug-induced liver injury (DILI) is a major clinical problem and its pathogenesis is poorly under... more Drug-induced liver injury (DILI) is a major clinical problem and its pathogenesis is poorly understood. The association of DILI with polymorphisms in hepatobiliary transport systems suggests a role for transport proteins in the pathogenesis of DILI. To investigate expression and tissue distribution of hepatobiliary transport systems in DILI. Expression of the canalicular bile salt export pump BSEP (ABCC11), phospholipid flippase MDR3 (ABCB4) and bilirubin export pump MRP2 (ABCC2) was assessed immunohistochemically in liver biopsies from 23 patients with DILI. Of 12 patients with cholestatic DILI (mostly due to antibiotics), 8 displayed a marked reduction of MRP2, MDR3 and BSEP expression. Transporter staining was normal in 4 patients with cholestatic DILI. In 11 patients with necroinflammatory hepatocellular injury (most frequently caused by NSAIDs), transporter staining was normal in areas where hepatocyte morphology was preserved. Due to hepatocyte necrosis and the reduction of th...

Drug metabolism and disposition: the biological fate of chemicals, 2014

The enterohepatic circulation of bile acids (BAs) critically depends on absorption of BA in the t... more The enterohepatic circulation of bile acids (BAs) critically depends on absorption of BA in the terminal ileum and colon, which can be affected by inflammatory bowel disease (IBD). Diarrhea in IBD is believed to result in part from BA malabsorption (BAM). We explored whether IBD alters mRNA expression of key intestinal BA transporters, BA detoxifying systems, and nuclear receptors that regulate BA transport and detoxification. Using real-time polymerase chain reaction, mucosal biopsy specimens from the terminal ileum in Crohn's disease (CD) patients and from the descending colon in ulcerative colitis (UC) patients were assessed for mRNA expression. Levels were compared with healthy controls. The main ileal BA uptake transporter, the apical sodium dependent bile acid transporter, was downregulated in active CD and UC and in CD in remission. Other significant changes such as repression of breast cancer-related protein and sulphotransferase 2A1 were seen only during active disease....

Hepatology International, 2014

Purpose Impaired vitamin D receptor signaling represents an aggravating factor during liver injur... more Purpose Impaired vitamin D receptor signaling represents an aggravating factor during liver injury, and recent studies suggest that vitamin D might exert a protective role in chronic hepatobiliary diseases. We hypothesized that vitamin D supplementation would ameliorate liver fibrosis in ATP-binding cassette transporter B4 knockout (Abcb4 -/-) mice as a preclinical model of sclerosing cholangitis. Methods Abcb4 -/and wild-type mice were fed a regular chow diet (600 IU vitamin D/kg food) or diets with lower (100 IU/kg) and higher (2,400 IU/kg) vitamin D concentrations for 12 weeks. Serum 25-hydroxyvitamin D concentrations were measured by chemiluminescence immunoassays. Liver injury and biliary fibrosis were assessed by liver enzyme activities, histopathology and hepatic collagen contents. Hepatic mRNA expression of markers for fibrosis, vitamin D and bile acid metabolism were analyzed by quantitative PCR. Results Different vitamin D concentrations were observed depending on genotype and diet group, with Abcb4 -/mice on the control diet showing lower vitamin D concentrations compared to wild-type mice. Abcb4 -/animals on the low vitamin D diet demonstrated the most advanced liver fibrosis and highest hepatic collagen contents. Feeding Abcb4 -/mice a high vitamin D diet enriched serum vitamin D levels, lowered liver enzyme activities, altered expression levels of profibrogenic genes and ameliorated, in part, liver injury. Conclusions This is the first report to demonstrate that fibrogenesis in the established Abcb4 -/model is influenced by vitamin D supplementation. Since vitamin D modulates sclerosing cholangitis in vivo, we speculate that sufficient vitamin D intake might improve liver damage and induce antifibrotic effects in chronic cholestasis in humans.

Journal of Hepatology, 2014

Case Reports in Hepatology, 2013

Nocardiosis is an infrequent but serious pulmonary infection caused by Gram-positive aerobic acti... more Nocardiosis is an infrequent but serious pulmonary infection caused by Gram-positive aerobic actinomycetes. In this paper, we report on a 48-year-old patient with pleuropulmonary nocardiosis and cirrhosis due to chronic hepatitis C virus infection treated with triple antiviral treatment complicated by prolonged neutropenia.

The American Journal of Gastroenterology, 1998

Intolerance to azathioprine is a rare but important problem in treating chronically active Crohn&... more Intolerance to azathioprine is a rare but important problem in treating chronically active Crohn's disease. We performed this study to evaluate mycophenolate mofetil as an alternative immunosuppressive therapy for patients with Crohn's disease who did not tolerate azathioprine. Four patients with highly active perianal Crohn's disease and two patients with chronically active, steroid-dependent Crohn's disease were included. All patients consumed 2 g/day of mycophenolate mofetil for a median of 8 months (range, 6-12 months). Disease activity was measured by the Perianal Crohn's Disease Activity Index in patients with perianal disease and by the Crohn's Disease Activity Index in patients with chronically active Crohn's disease. Azathioprine-induced side effects disappeared after the drug was discontinued. All patients improved during treatment with mycophenolate mofetil, as shown by a remarkable reduction in the respective clinical scores. Five patients showed no side effects during treatment with mycophenolate mofetil. After 4 months' treatment one patient developed diarrhea that was probably not due to mycophenolate mofetil. Mycophenolate mofetil could be an alternative therapy to azathioprine in patients with Crohn's disease.

Wiener klinische Wochenschrift, Jan 4, 2014

Abstract Abstract Abstract AIM: NONI juice (Morinda citrifolia) is an increasingly popular wellne... more Abstract Abstract Abstract AIM: NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed.

Zeitschrift für Gastroenterologie, 2008

Seminars in Liver Disease, 2007

Because ATP-binding cassette (ABC) transporters are important for normal bile secretion, heredita... more Because ATP-binding cassette (ABC) transporters are important for normal bile secretion, hereditary and acquired ABC transporter defects play a central role in the pathogenesis of cholestasis. Defects of the phospholipid export pump MDR3 ( ABCC4) result in impaired biliary excretion of phosphatidylcholine and a variety of cholestatic syndromes ranging from progressive familial intrahepatic cholestasis in neonates to biliary cirrhosis in adults. Moreover, MDR3 mutations predispose to cholestasis of pregnancy and drug-induced cholestasis. Because MDR2 (rodent orthologue of human MDR3) knockout mice develop sclerosing cholangitis, it is attractive to speculate that MDR3 defects could also play an important role in cholangiopathies in humans. Indeed, MDR3 variants could play a role as modifier gene in primary biliary cirrhosis and primary sclerosing cholangitis, but their exact role needs further clarification. Impaired biliary phosphatidylcholine excretion has also been reported in total parenteral nutrition-induced cholestasis and bile duct injury following liver transplantation, but a genetic basis for these findings remains to be explored. Several drugs for the treatment of cholestatic liver diseases target MDR3 expression and function, further underscoring the clinical significance of this transport system.

Liver International, 2007

Bile acid synthesis, transport and metabolism are markedly altered in experimental cholestasis. W... more Bile acid synthesis, transport and metabolism are markedly altered in experimental cholestasis. Whether such coordinated regulation exists in human cholestatic diseases is unclear. We therefore investigated expression of genes for bile acid synthesis, detoxification and alternative basolateral export and regulatory nuclear factors in primary biliary cirrhosis (PBC). Hepatic CYP7A1, CYP27A1, CYP8B1 (bile acid synthesis), CYP3A4 (hydroxylation), SULT2A1 (sulphation), UGT2B4/2B7 (glucuronidation), MRP4 (basolateral export), farnesoid X receptor (FXR), retinoid X receptor (RXR), short heterodimer partner (SHP), hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF4alpha expression was determined in 11 patients with late-stage PBC and this was compared with non-cholestatic controls. CYP7A1 mRNA was repressed in PBC to 10-20% of controls, while CYP27 and CYP8B1 mRNA remained unchanged. SULT2A1, UGT2B4/2B7 and CYP3A4 mRNA levels were unaltered or only mildly reduced in PBC. MRP4 protein levels were induced three-fold in PBC, whereas mRNA levels remained unchanged. Expression levels of FXR, RXR, SHP, PXR, CAR, HNF1alpha and HNF4alpha were moderately reduced in PBC without reaching statistical significance. Repression of bile acid synthesis and induction of basolateral bile acid export may represent adaptive mechanisms to limit bile acid burden in chronic cholestasis. As these changes do not sufficiently counteract cholestatic liver damage, future therapeutic strategies should aim at stimulation of bile acid detoxification pathways.

Liver International, 2005

Treatment of hepatocellular carcinoma (HCC) is hampered by resistance to chemotherapy, which migh... more Treatment of hepatocellular carcinoma (HCC) is hampered by resistance to chemotherapy, which might be mediated by multidrug resistance P-glycoproteins (MDR P-gps) and MDR-associated proteins (MRPs). The effectiveness of cytostatics could be further impeded by reduced hepatocellular drug uptake into HCCs. Therefore, we aimed to determine P-gp, MRP and organic anion transporting protein OATP2 (SLC21A6) expression in HCC. Furthermore, we investigated expression of the major bile salt uptake system Na(+)/taurocholate cotransporter NTCP (SLC10A1), since bile salt-coupled chemotherapeutics were proposed to increase therapeutic drug enrichment in HCC. mRNA and protein expression and tissue distribution of P-gps, MRPs, OATP2 and NTCP were assessed in HCC and peritumorous non-neoplastic tissue by reverse transcription polymerase chain reaction, Western blotting and immunohistochemistry, respectively. Expression of P-gps (multidrug export pump MDR1 (ABCB1), phospholipid flippase MDR3 (ABCB4), sister of P-glycoprotein SPGP (ABCB11)) and basolateral MRP homologue MRP3 (ABCC3) showed a trend for decreased levels in HCC but was highly variable among individual tumors. In contrast, canalicular conjugate export pump MRP2 (ABCC2) expression was generally maintained or even showed a trend towards increased levels. NTCP and OATP2 expression was markedly reduced in most HCCs (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Expression of the genuine drug transporter, the concentrative nucleoside transporter (CNT1), was highly variable and showed a trend for reduced levels in HCC. MRP2 seems to be the major candidate transporter involved in chemoresistance and reduced expression of OATP2 may further contribute to low drug accumulation in HCCs. Overexpression of drug exporters is not a general feature of HCC but could account for chemoresistance of individual cases. Since expression of uptake systems is generally reduced in HCC, bile salt-coupled therapeutics may not represent a suitable strategy to overcome insufficient drug enrichment.

Liver International, 2012

Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with hig... more Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with high morbidity and mortality. Apart from different known factors responsible for the development of post-operative jaundice, little is known about the role of hepatobiliary transport systems in the pathogenesis of post-operative jaundice in humans after liver resection. Two liver tissue samples were taken from 14 patients undergoing liver resection before and after Pringle manoeuvre. Patients were retrospectively divided into two groups according to post-operative bilirubin serum levels. The two groups were analysed comparing the results of hepatobiliary transporter [Na-taurocholate cotransporter (NTCP); multidrug resistance gene/phospholipid export pump(MDR3); bile salt export pump (BSEP); canalicular bile salt export pump (MRP2)], heat shock protein 70 (HSP70) expression as well as the results of routinely taken post-operative liver chemistry tests. Patients with low post-operative bilirubin had lower levels of NTCP, MDR3 and BSEP mRNA compared to those with high bilirubin after Pringle manoeuvre. HSP70 levels were significantly higher after ischaemia-reperfusion (IR) injury in both groups resulting in 4.5-fold median increase. Baseline median mRNA expression of all four transporters prior to Pringle manoeuvre tended to be lower in the low bilirubin group whereas expression of HSP70 was higher in the low bilirubin group compared to the high bilirubin group. Higher mRNA levels of HSP70 in the low bilirubin group could indicate a possible protective effect of high HSP70 levels against IR injury. Although the exact role of hepatobiliary transport systems in the development of post-operative hyper bilirubinemia is not yet completely understood, this study provides new insights into the molecular aspects of post-operative jaundice after liver surgery.

The Journal of Pathology, 2004

The keratin intermediate filament (IF) cytoskeleton of hepatocytes has continuously gained medica... more The keratin intermediate filament (IF) cytoskeleton of hepatocytes has continuously gained medical relevance over the last two decades. Originally it was mainly recognized as a differentiation marker for diagnostic purposes in pathology. However, keratin IFs were soon identified as major cellular structures to be affected in a variety of chronic liver diseases, such as alcoholic and non-alcoholic steatohepatitis (ASH, NASH), copper toxicosis, and cholestasis. Based on observations in keratin gene knock-out mice, the insight into the functional role of keratins was extended from a mere structural role providing mechanical stability to hepatocytes, to an additional role as target and modulator of toxic stress and apoptosis. The functional relevance of keratins in human diseases has recently been underlined by the identification of mutations in keratin genes in patients with liver cirrhosis.