Peter Jansen | University of Amsterdam (original) (raw)

Papers by Peter Jansen

Research paper thumbnail of Alterations of Hormonally Active Fibroblast Growth Factors after Roux-en-Y Gastric Bypass Surgery

Digestive Diseases, 2011

Thirty-five morbidly obese patients underwent Roux-en-Y gastric bypass surgery (RYGB). In additio... more Thirty-five morbidly obese patients underwent Roux-en-Y gastric bypass surgery (RYGB). In addition to weight loss, these patients showed significant improvement of insulin resistance and a reduction of hepatic fat content. Three months after surgery, the serum bile salts were slightly but significantly elevated, and the levels of the endocrine-acting fibroblast growth factor 19 (FGF19) and FGF21 were increased. FGF19 and FGF21 play a role as regulators of hepatic lipid and glucose metabolism. These results show that RYGB surgery improves metabolism and that this improvement is still apparent 3 months after surgery. Bile salts may play a key role in the improvement of metabolism after RYGB. Why serum bile salt concentrations are elevated after RYGB needs to be investigated.

Research paper thumbnail of Accumulation of organic anion in intracellular vesicles of cultured rat hepatocytes is mediated by the canalicular multispecific organic anion transporter

Hepatology, 1993

Transport of organic anions within hepatocytes and the possible involvement of intracellular vesi... more Transport of organic anions within hepatocytes and the possible involvement of intracellular vesicles were studied with fluorescence microscopy. For this purpose monochlorobimane, a nonfluorescent hydrophobic compound that readily permeates into cells and is conjugated with glutathione to form the fluorescent glutathione bimane, was used. In the isolated perfused livers of normal rats, glutathione bimane is rapidly secreted into bile. In contrast, in our study of livers from mutant TR- rats, a 100-fold reduction in glutathione bimane secretion into bile occurred. Mutant TR- rats have an inherited defect in the canalicular multispecific organic anion transporter, which mediates the ATP-dependent secretion of a wide range of organic anions over the canalicular membrane into bile. When cultured Wistar and TR- hepatocytes were loaded with glutathione bimane, both cell types displayed a strong cytosolic fluorescence. Wistar cells completely lost this cytosolic fluorescence at incubation on monochlorobimane-free medium because of secretion of glutathione bimane. A clear punctate fluorescence remained, however, which was scattered through the cell with some perinuclear concentration. In some cells vesicular fluorescence was also concentrated around a canaliculus. In contrast, TR- cells lost their cytosolic fluorescence more slowly and completely lacked the vesicular fluorescence. Making cells selectively permeable with digitonin directly after loading them with glutathione bimane to remove cytosolic fluorescence again revealed the presence of fluorescent vesicles in Wistar cells and their absence in TR- cells. In Wistar cells vesicular fluorescence could be increased by preincubation with monensin or methylamine, compounds that have been shown to interfere with plasma membrane recycling. In conclusion, these results suggest that apart from secretion over the plasma membrane, the canalicular multispecific organic anion transporter may be involved in accumulation of organic anion in intracellular vesicles. It is hypothesized that this intracellular localization of the canalicular multispecific organic anion transporter is caused by recycling of the transporter between the plasma membrane and intracellular membranes.

Research paper thumbnail of The human gallbladder secretes fibroblast growth factor 19 into bile: Towards defining the role of fibroblast growth factor 19 in the enterobiliary tract

Hepatology, 2012

Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of b... more Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of bile salt synthesis. In the postprandial state, activation of ileal farnesoid X receptor (FXR) by bile salts results in transcriptional induction of FGF19 and elevation of circulating FGF19 levels. An intestinal-liver axis of FGF19 signaling results in down-regulation of bile salt synthesis. The aim of this study was to explore a broader signaling activity of FGF19 in organs engaged in the enterohepatic circulation of bile salts. For this aim, FGF19 expression and aspects of FGF19 signaling were studied in surgical specimens and in cell lines of hepatobiliary and intestinal origin. FGF19 messenger RNA was found to be abundantly expressed in the human gallbladder and in the common bile duct, with only minor expression observed in the ileum. Interestingly, human gallbladder bile contains high levels of FGF19 (21.9 6 13.3 versus 0.22 6 0.14 ng/mL in the systemic circulation). Gallbladder explants secrete 500 times more FGF19 than FXR agonist-stimulated ileal explants. Factors required for FGF19 signaling (i.e., FGFR4 and bKlotho) are expressed in mucosal epithelial cells of the gallbladder and small intestine. FGF19 was found to activate signaling pathways in cell lines of cholangiocytic, enteroendocrine, and enterocytic origin. Conclusion: The combined findings raise the intriguing possibility that biliary FGF19 has a signaling function in the biliary tract that differs from its established signaling function in the portal circulation. Delineation of the target cells in bile-exposed tissues and the affected cellular pathways, as well as a possible involvement in biliary tract disorders, require further studies. (HEPATOLOGY 2012;55:575-583)

Research paper thumbnail of Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11

Gastroenterology, Aug 1, 2004

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intr... more Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are hereditary liver disorders; PFIC is characterized by severe progressive liver disease whereas BRIC patients have intermittent attacks of cholestasis without permanent liver damage. Mutations in ATP8B1 are present in PFIC type 1 and in a subset of BRIC patients. We hypothesized that a genetically distinct form of BRIC is associated with mutations in ABCB11. This gene encodes the bile salt export pump (BSEP) and is mutated in PFIC type 2. Methods: Patients from 20 families were included; all had a normal ATP8B1 sequence. Sequencing of all 27 coding exons including the splice junctions of ABCB11 revealed 8 distinct mutations in 11 patients from 8 different families: one homozygous missense mutation (E297G) previously described in PFIC2 patients, 6 novel missense mutations, and one putative splice site mutation. Results: In 12 families, no mutations in ATB8B1 or ABCB11 were detected. Pancreatitis is a known extrahepatic symptom in BRIC caused by ATP8B1 mutations, but was not present in BRIC patients with mutations in ABCB11. In contrast, cholelithiasis was observed in 7 of 11 BRIC patients with mutations in ABCB11, but has not been described in ATP8B1-affected BRIC patients. Conclusions: Mutations in ABCB11 are associated with BRIC, and consistent with the genetic classification of PFIC into 2 subtypes, we propose that this disorder be named BRIC type 2.

Research paper thumbnail of The SPGP gene, encoding the canalicular bile acid transporting protein SPGP/cBST, is not expressed in a subgroup of patients with progressive familial intrahepatic cholestasis (PFIC-2)

Research paper thumbnail of The expression of inducible nitric oxide synthase (iNOS) in intestinal epithelial cells is regulated by NF-KB and is dependent on the intracellular redox status

European Journal of Gastroenterology Hepatology, 1999

Research paper thumbnail of Ultrawideband Radar Measurements of Thickness of Snow Over Sea Ice

Ieee Transactions on Geoscience and Remote Sensing, Sep 1, 2007

An accurate knowledge of snow thickness and its variability over sea ice is crucial in determinin... more An accurate knowledge of snow thickness and its variability over sea ice is crucial in determining the overall polar heat and freshwater budget, which influences the global climate. Recently, algorithms have been developed to extract snow thicknesses from satellite passive microwave data. However, validation of these data over the large footprint of the passive microwave sensor has been a challenge. The only method used thus far has been with meter sticks during ship cruises. To address this problem, we developed an ultrawideband frequency-modulated continuous-wave radar to measure the snow thickness over sea ice. We synthesized a very linear chirp signal by using a phase-locked loop with a digitally generated chirp signal as a reference to obtain a fine-range resolution. The radar operates over the frequency range from 2-8 GHz. We made snow-thickness measurements over the Antarctic sea ice by operating the radar from a sled in September and October 2003. We performed radar measurements over 11 stations with varying snow thicknesses between 4 and 85 cm. We observed an excellent agreement between radar estimates of snow thickness with physical measurements, achieving a correlation coefficient of 0.95 and a vertical resolution of about 3 cm. Comparison of simulated radar waveforms using a simple transmission line model with the measurements confirms our expectations that echoes from snow-covered sea ice are dominated by reflections from air-snow and snow-ice interfaces.

Research paper thumbnail of Prometheus' little helper, a novel role for fibroblast growth factor 15 in compensatory liver growth

Journal of Hepatology, Jul 15, 2013

Objective: Cholestasis is associated with increased liver injury and morbidity after partial hepa... more Objective: Cholestasis is associated with increased liver injury and morbidity after partial hepatectomy (PH), yet bile acids (BAs) are emerging as important mediators of liver regeneration. Fibroblast growth factor 15 (Fgf15, human FGF19) is a BA-induced ileum-derived enterokine that governs BA metabolism. We evaluated the relevance of Fgf15 in the preservation of BA homeostasis after PH and its potential role in the regenerative process. Design: Liver regeneration after PH was studied in Fgf15 À/À and Fgf15 +/+ mice. The effects of the BA sequestrant cholestyramine and adenovirally delivered Fgf15 were examined in this model. The role of Fgf15 in BAinduced liver growth was tested in Fgf15 À/À mice upon cholic acid (CA) feeding. The direct mitogenic effect of Fgf15 was evaluated in cultured mouse hepatocytes and cholangiocytes. Results: Fgf15 À/À mice showed marked liver injury and mortality after PH accompanied by persistently elevated intrahepatic BA levels. Cholestyramine feeding and adenovirally delivered Fgf15 reduced BA levels and significantly prevented this lethal outcome. Fgf15 also reduced mortality after extensive hepatectomy in Fgf15 +/+ animals. Liver growth elicited by CA feeding was significantly diminished in Fgf15 À/À mice. Proliferation of hepatocytes and cholangiocytes was also noticeably reduced in CA-fed Fgf15 À/À mice. Fgf15 induced intracellular signaling and proliferation of cultured hepatocytes and cholangiocytes.

Research paper thumbnail of Human Bile Contains High Levels of the Endocrine Factor FGF19. Potential Role of FGF19 in the Entero-Hepatobiliary System

Research paper thumbnail of Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

Palliative Medicine, 2006

Background/Aims: In liver diseases, reactive oxygen species (ROS) are involved in cell death and ... more Background/Aims: In liver diseases, reactive oxygen species (ROS) are involved in cell death and liver injury, but the mechanisms are not completely elucidated. To elucidate the mechanisms of hepatocyte cell death induced by the ROS superoxide anions and hydrogen peroxide, primary cultures of hepatocytes were exposed to the superoxide anion donor menadione (10-50 mu mol/L) or H2O2 (1-5 mmol/L). Hepatocytes

Research paper thumbnail of Surveillance for hepatocellular carcinoma is associated with increased survival: Results from a large cohort in the Netherlands

Journal of Hepatology, 2015

Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its ... more Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its effects in "real life" clinical practice. Patients with hepatocellular carcinoma diagnosed in the period 2005-2012 in five Dutch academic centers were evaluated. Surveillance was defined as ⩾2 screening tests during 3 preceding years and at least one radiologic imaging test within 18 months before diagnosis. 295 (27%) of 1074 cases underwent surveillance. Median time interval between last negative radiologic imaging and hepatocellular carcinoma diagnosis was 7.5 months. In the surveillance group, cirrhosis (97% vs. 60%, P<0.001) and viral hepatitis were more frequent and non-alcoholic fatty liver disease or absence of risk factors less frequent. In case of surveillance, tumor size was significantly smaller (2.7 vs. 6.0 cm), with lower alpha-fetoprotein levels (16 vs. 44 μg/L), earlier tumor stage (BCLC 0 and A combined: 61% vs. 21%) and resection/transplantation (34% vs. 25%) or radiofrequency ablation (23% vs. 7%) more often applied, with significantly higher 1-, 3- and 5-year survival rates. Survival benefit by surveillance remained significant after adjustment for lead-time bias based on assumed tumor doubling time of 90 days, but not with doubling time of ⩾120 days. In multivariate analysis, surveillance was an independent predictor for mortality (for interval ⩽9 respectively >9 months: adjusted hazard ratios 0.51 and 0.50, 95% confidence intervals: 0.39-0.67 and 0.37-0.69). Surveillance for hepatocellular carcinoma was associated with smaller tumor size, earlier tumor stage, with impact on therapeutic strategy and was an independent predictor of survival.

Research paper thumbnail of Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity

Obesity, 2015

Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for ca... more Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for cardiovascular disease in adults. It has not been established whether NAFLD is related to early atherosclerotic changes in children. In a cross-sectional study, 78 non diabetic, non smoking children with severe obesity were evaluated for NAFLD. Proton magnetic resonance spectroscopy was used to detect liver steatosis and serum ALT was used as a surrogate marker for steatohepatitis. Carotid intima-media thickness (CIMT) and arterial wall stiffness were measured using ultrasound. Steatosis was present in 41 (53%) of subjects. Of these children, 26 out of 41 (63%) had elevated ALT levels. No differences in CIMT and arterial wall stiffness were observed between those without and with steatosis and those with steatosis plus elevated ALT levels [CIMT = 0.47 (±0.06), 0.48 (±0.06) and 0.48 (±0.07) mm, respectively; stiffness = 2.78 (±0.50), 3.00 (±0.81), and 2.90 (±0.78), respectively]. Steatosis and ALT were not correlated to CIMT (r = -0.02 and -0.14, respectively) or arterial wall stiffness (r = 0.13 and -0.11, respectively). In this study, no relationship between NAFLD and early atherosclerotic changes in children was observed. An atherogenic effect of steatohepatitis (NASH) on pediatric age and long-term atherogenic consequences of simple steatosis cannot be excluded based on this study.

Research paper thumbnail of New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond

Journal of hepatology, 2015

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholang... more Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors ...

Research paper thumbnail of Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity

Obesity (Silver Spring, Md.), Jan 9, 2015

Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for ca... more Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for cardiovascular disease in adults. It has not been established whether NAFLD is related to early atherosclerotic changes in children. In a cross-sectional study, 78 non diabetic, non smoking children with severe obesity were evaluated for NAFLD. Proton magnetic resonance spectroscopy was used to detect liver steatosis and serum ALT was used as a surrogate marker for steatohepatitis. Carotid intima-media thickness (CIMT) and arterial wall stiffness were measured using ultrasound. Steatosis was present in 41 (53%) of subjects. Of these children, 26 out of 41 (63%) had elevated ALT levels. No differences in CIMT and arterial wall stiffness were observed between those without and with steatosis and those with steatosis plus elevated ALT levels [CIMT = 0.47 (±0.06), 0.48 (±0.06) and 0.48 (±0.07) mm, respectively; stiffness = 2.78 (±0.50), 3.00 (±0.81), and 2.90 (±0.78), respectively]. Steatosis ...

Research paper thumbnail of New developments in the antiviral treatment of hepatitis C

Vox sanguinis, 2009

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular ... more Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is endemic in most parts of the world, with an estimated 170 million people infected worldwide and 3-4 million new cases each year. HCV-related end-stage liver disease is now the main indication for liver transplantation in the USA and Western Europe. Unfortunately, no vaccine or immunoglobulin is available to prevent HCV infection. Currently, HCV treatment consists of the combined administration of pegylated interferon and ribavirin for a period of 24-48 weeks, resulting in complete viral eradication in 40-80% of patients, depending on genotype, viral load and patient characteristics. This therapy is often accompanied with side-effects that affect compliance and reduce treatment outcomes. Recently, reliable in vitro culture systems have been developed which accelerated antiviral therapy research. Many new specifically targeted antiviral therapies for hepatitis C (STAT-C) ...

Research paper thumbnail of Determination of ammonia in cerebrospinal fluid using the indophenol direct method

Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid

We have determined ammonia in cerebrospinal fluid (CSF) with the indophenol direct method. The re... more We have determined ammonia in cerebrospinal fluid (CSF) with the indophenol direct method. The results were compared with an enzymatic method. The method is very simple, and precision (coefficient of variation 1.6%) and linearity (r = 0.9999, p < 0.001) of the method are excellent. The recoveries of the method are very good (within-sample recovery: range 88-93, median 93%; between-sample recovery: 88-93, median 91%). In a population of 23 neurological patients not suffering from liver disease, the reference values ranged from 8 to 26, median 18 microM. Males and females did not differ (p = 0.5). The values obtained with the indophenol method were equal to the enzymatic method (range 9-28, median 18 microM, p = 0.6). On storage in the deep freeze (-20 degrees C), there was no change in CSF ammonia concentration for at least 1 mo. When stored at 4 degrees C (refrigerator), ammonia determinations have to be performed within 2 d. CSF storage at room temperature results in artificiall...

Research paper thumbnail of Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells

Liver International, 2001

Moshage H. Involvement of reactive oxygen species and nitric oxide Stefania Saccomanno 1 , radica... more Moshage H. Involvement of reactive oxygen species and nitric oxide Stefania Saccomanno 1 , radicals in activation and proliferation of rat hepatic stellate cells. Abstract: Background /Aims: Reactive oxygen species (ROS) induce HSCs ide (NO) represents a reactive molecule that reacts with ROS, yielding Gastroenterology and Hepatology, University peroxynitrite. We thus verified the effect of NO on ROS-induced HSCs Hospital Groningen, The Netherlands

Research paper thumbnail of Mechanisms of Bile Formation: An Introduction

Molecular Pathogenesis of Cholestasis, 2004

Research paper thumbnail of Monitoring of Total and Regional Liver Function after SIRT

Frontiers in oncology, 2014

Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepato... more Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepatocellular carcinoma or metastatic liver cancer. SIRT is usually well tolerated. However, in most patients, SIRT will result in a (temporary) decreased liver function. Occasionally patients develop radioembolization-induced liver disease (REILD). In case of a high tumor burden of the liver, it could be beneficial to perform SIRT in two sessions enabling the primary untreated liver segments to guarantee liver function until function in the treated segments has recovered or functional hypertrophy has occurred. Clinically used liver function tests provide evidence of only one of the many liver functions, though all of them lack the possibility of assessment of segmental (regional) liver function. Hepatobiliary scintigraphy (HBS) has been validated as a tool to assess total and regional liver function in liver surgery. It is also used to assess segmental liver function before and after portal ...

Research paper thumbnail of Bile acid receptors as targets for drug development

Nature Reviews Gastroenterology & Hepatology, 2013

| The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled... more | The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.

Research paper thumbnail of Alterations of Hormonally Active Fibroblast Growth Factors after Roux-en-Y Gastric Bypass Surgery

Digestive Diseases, 2011

Thirty-five morbidly obese patients underwent Roux-en-Y gastric bypass surgery (RYGB). In additio... more Thirty-five morbidly obese patients underwent Roux-en-Y gastric bypass surgery (RYGB). In addition to weight loss, these patients showed significant improvement of insulin resistance and a reduction of hepatic fat content. Three months after surgery, the serum bile salts were slightly but significantly elevated, and the levels of the endocrine-acting fibroblast growth factor 19 (FGF19) and FGF21 were increased. FGF19 and FGF21 play a role as regulators of hepatic lipid and glucose metabolism. These results show that RYGB surgery improves metabolism and that this improvement is still apparent 3 months after surgery. Bile salts may play a key role in the improvement of metabolism after RYGB. Why serum bile salt concentrations are elevated after RYGB needs to be investigated.

Research paper thumbnail of Accumulation of organic anion in intracellular vesicles of cultured rat hepatocytes is mediated by the canalicular multispecific organic anion transporter

Hepatology, 1993

Transport of organic anions within hepatocytes and the possible involvement of intracellular vesi... more Transport of organic anions within hepatocytes and the possible involvement of intracellular vesicles were studied with fluorescence microscopy. For this purpose monochlorobimane, a nonfluorescent hydrophobic compound that readily permeates into cells and is conjugated with glutathione to form the fluorescent glutathione bimane, was used. In the isolated perfused livers of normal rats, glutathione bimane is rapidly secreted into bile. In contrast, in our study of livers from mutant TR- rats, a 100-fold reduction in glutathione bimane secretion into bile occurred. Mutant TR- rats have an inherited defect in the canalicular multispecific organic anion transporter, which mediates the ATP-dependent secretion of a wide range of organic anions over the canalicular membrane into bile. When cultured Wistar and TR- hepatocytes were loaded with glutathione bimane, both cell types displayed a strong cytosolic fluorescence. Wistar cells completely lost this cytosolic fluorescence at incubation on monochlorobimane-free medium because of secretion of glutathione bimane. A clear punctate fluorescence remained, however, which was scattered through the cell with some perinuclear concentration. In some cells vesicular fluorescence was also concentrated around a canaliculus. In contrast, TR- cells lost their cytosolic fluorescence more slowly and completely lacked the vesicular fluorescence. Making cells selectively permeable with digitonin directly after loading them with glutathione bimane to remove cytosolic fluorescence again revealed the presence of fluorescent vesicles in Wistar cells and their absence in TR- cells. In Wistar cells vesicular fluorescence could be increased by preincubation with monensin or methylamine, compounds that have been shown to interfere with plasma membrane recycling. In conclusion, these results suggest that apart from secretion over the plasma membrane, the canalicular multispecific organic anion transporter may be involved in accumulation of organic anion in intracellular vesicles. It is hypothesized that this intracellular localization of the canalicular multispecific organic anion transporter is caused by recycling of the transporter between the plasma membrane and intracellular membranes.

Research paper thumbnail of The human gallbladder secretes fibroblast growth factor 19 into bile: Towards defining the role of fibroblast growth factor 19 in the enterobiliary tract

Hepatology, 2012

Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of b... more Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of bile salt synthesis. In the postprandial state, activation of ileal farnesoid X receptor (FXR) by bile salts results in transcriptional induction of FGF19 and elevation of circulating FGF19 levels. An intestinal-liver axis of FGF19 signaling results in down-regulation of bile salt synthesis. The aim of this study was to explore a broader signaling activity of FGF19 in organs engaged in the enterohepatic circulation of bile salts. For this aim, FGF19 expression and aspects of FGF19 signaling were studied in surgical specimens and in cell lines of hepatobiliary and intestinal origin. FGF19 messenger RNA was found to be abundantly expressed in the human gallbladder and in the common bile duct, with only minor expression observed in the ileum. Interestingly, human gallbladder bile contains high levels of FGF19 (21.9 6 13.3 versus 0.22 6 0.14 ng/mL in the systemic circulation). Gallbladder explants secrete 500 times more FGF19 than FXR agonist-stimulated ileal explants. Factors required for FGF19 signaling (i.e., FGFR4 and bKlotho) are expressed in mucosal epithelial cells of the gallbladder and small intestine. FGF19 was found to activate signaling pathways in cell lines of cholangiocytic, enteroendocrine, and enterocytic origin. Conclusion: The combined findings raise the intriguing possibility that biliary FGF19 has a signaling function in the biliary tract that differs from its established signaling function in the portal circulation. Delineation of the target cells in bile-exposed tissues and the affected cellular pathways, as well as a possible involvement in biliary tract disorders, require further studies. (HEPATOLOGY 2012;55:575-583)

Research paper thumbnail of Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11

Gastroenterology, Aug 1, 2004

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intr... more Background & Aims: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are hereditary liver disorders; PFIC is characterized by severe progressive liver disease whereas BRIC patients have intermittent attacks of cholestasis without permanent liver damage. Mutations in ATP8B1 are present in PFIC type 1 and in a subset of BRIC patients. We hypothesized that a genetically distinct form of BRIC is associated with mutations in ABCB11. This gene encodes the bile salt export pump (BSEP) and is mutated in PFIC type 2. Methods: Patients from 20 families were included; all had a normal ATP8B1 sequence. Sequencing of all 27 coding exons including the splice junctions of ABCB11 revealed 8 distinct mutations in 11 patients from 8 different families: one homozygous missense mutation (E297G) previously described in PFIC2 patients, 6 novel missense mutations, and one putative splice site mutation. Results: In 12 families, no mutations in ATB8B1 or ABCB11 were detected. Pancreatitis is a known extrahepatic symptom in BRIC caused by ATP8B1 mutations, but was not present in BRIC patients with mutations in ABCB11. In contrast, cholelithiasis was observed in 7 of 11 BRIC patients with mutations in ABCB11, but has not been described in ATP8B1-affected BRIC patients. Conclusions: Mutations in ABCB11 are associated with BRIC, and consistent with the genetic classification of PFIC into 2 subtypes, we propose that this disorder be named BRIC type 2.

Research paper thumbnail of The SPGP gene, encoding the canalicular bile acid transporting protein SPGP/cBST, is not expressed in a subgroup of patients with progressive familial intrahepatic cholestasis (PFIC-2)

Research paper thumbnail of The expression of inducible nitric oxide synthase (iNOS) in intestinal epithelial cells is regulated by NF-KB and is dependent on the intracellular redox status

European Journal of Gastroenterology Hepatology, 1999

Research paper thumbnail of Ultrawideband Radar Measurements of Thickness of Snow Over Sea Ice

Ieee Transactions on Geoscience and Remote Sensing, Sep 1, 2007

An accurate knowledge of snow thickness and its variability over sea ice is crucial in determinin... more An accurate knowledge of snow thickness and its variability over sea ice is crucial in determining the overall polar heat and freshwater budget, which influences the global climate. Recently, algorithms have been developed to extract snow thicknesses from satellite passive microwave data. However, validation of these data over the large footprint of the passive microwave sensor has been a challenge. The only method used thus far has been with meter sticks during ship cruises. To address this problem, we developed an ultrawideband frequency-modulated continuous-wave radar to measure the snow thickness over sea ice. We synthesized a very linear chirp signal by using a phase-locked loop with a digitally generated chirp signal as a reference to obtain a fine-range resolution. The radar operates over the frequency range from 2-8 GHz. We made snow-thickness measurements over the Antarctic sea ice by operating the radar from a sled in September and October 2003. We performed radar measurements over 11 stations with varying snow thicknesses between 4 and 85 cm. We observed an excellent agreement between radar estimates of snow thickness with physical measurements, achieving a correlation coefficient of 0.95 and a vertical resolution of about 3 cm. Comparison of simulated radar waveforms using a simple transmission line model with the measurements confirms our expectations that echoes from snow-covered sea ice are dominated by reflections from air-snow and snow-ice interfaces.

Research paper thumbnail of Prometheus' little helper, a novel role for fibroblast growth factor 15 in compensatory liver growth

Journal of Hepatology, Jul 15, 2013

Objective: Cholestasis is associated with increased liver injury and morbidity after partial hepa... more Objective: Cholestasis is associated with increased liver injury and morbidity after partial hepatectomy (PH), yet bile acids (BAs) are emerging as important mediators of liver regeneration. Fibroblast growth factor 15 (Fgf15, human FGF19) is a BA-induced ileum-derived enterokine that governs BA metabolism. We evaluated the relevance of Fgf15 in the preservation of BA homeostasis after PH and its potential role in the regenerative process. Design: Liver regeneration after PH was studied in Fgf15 À/À and Fgf15 +/+ mice. The effects of the BA sequestrant cholestyramine and adenovirally delivered Fgf15 were examined in this model. The role of Fgf15 in BAinduced liver growth was tested in Fgf15 À/À mice upon cholic acid (CA) feeding. The direct mitogenic effect of Fgf15 was evaluated in cultured mouse hepatocytes and cholangiocytes. Results: Fgf15 À/À mice showed marked liver injury and mortality after PH accompanied by persistently elevated intrahepatic BA levels. Cholestyramine feeding and adenovirally delivered Fgf15 reduced BA levels and significantly prevented this lethal outcome. Fgf15 also reduced mortality after extensive hepatectomy in Fgf15 +/+ animals. Liver growth elicited by CA feeding was significantly diminished in Fgf15 À/À mice. Proliferation of hepatocytes and cholangiocytes was also noticeably reduced in CA-fed Fgf15 À/À mice. Fgf15 induced intracellular signaling and proliferation of cultured hepatocytes and cholangiocytes.

Research paper thumbnail of Human Bile Contains High Levels of the Endocrine Factor FGF19. Potential Role of FGF19 in the Entero-Hepatobiliary System

Research paper thumbnail of Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

Palliative Medicine, 2006

Background/Aims: In liver diseases, reactive oxygen species (ROS) are involved in cell death and ... more Background/Aims: In liver diseases, reactive oxygen species (ROS) are involved in cell death and liver injury, but the mechanisms are not completely elucidated. To elucidate the mechanisms of hepatocyte cell death induced by the ROS superoxide anions and hydrogen peroxide, primary cultures of hepatocytes were exposed to the superoxide anion donor menadione (10-50 mu mol/L) or H2O2 (1-5 mmol/L). Hepatocytes

Research paper thumbnail of Surveillance for hepatocellular carcinoma is associated with increased survival: Results from a large cohort in the Netherlands

Journal of Hepatology, 2015

Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its ... more Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its effects in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;real life&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; clinical practice. Patients with hepatocellular carcinoma diagnosed in the period 2005-2012 in five Dutch academic centers were evaluated. Surveillance was defined as ⩾2 screening tests during 3 preceding years and at least one radiologic imaging test within 18 months before diagnosis. 295 (27%) of 1074 cases underwent surveillance. Median time interval between last negative radiologic imaging and hepatocellular carcinoma diagnosis was 7.5 months. In the surveillance group, cirrhosis (97% vs. 60%, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and viral hepatitis were more frequent and non-alcoholic fatty liver disease or absence of risk factors less frequent. In case of surveillance, tumor size was significantly smaller (2.7 vs. 6.0 cm), with lower alpha-fetoprotein levels (16 vs. 44 μg/L), earlier tumor stage (BCLC 0 and A combined: 61% vs. 21%) and resection/transplantation (34% vs. 25%) or radiofrequency ablation (23% vs. 7%) more often applied, with significantly higher 1-, 3- and 5-year survival rates. Survival benefit by surveillance remained significant after adjustment for lead-time bias based on assumed tumor doubling time of 90 days, but not with doubling time of ⩾120 days. In multivariate analysis, surveillance was an independent predictor for mortality (for interval ⩽9 respectively &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;9 months: adjusted hazard ratios 0.51 and 0.50, 95% confidence intervals: 0.39-0.67 and 0.37-0.69). Surveillance for hepatocellular carcinoma was associated with smaller tumor size, earlier tumor stage, with impact on therapeutic strategy and was an independent predictor of survival.

Research paper thumbnail of Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity

Obesity, 2015

Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for ca... more Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for cardiovascular disease in adults. It has not been established whether NAFLD is related to early atherosclerotic changes in children. In a cross-sectional study, 78 non diabetic, non smoking children with severe obesity were evaluated for NAFLD. Proton magnetic resonance spectroscopy was used to detect liver steatosis and serum ALT was used as a surrogate marker for steatohepatitis. Carotid intima-media thickness (CIMT) and arterial wall stiffness were measured using ultrasound. Steatosis was present in 41 (53%) of subjects. Of these children, 26 out of 41 (63%) had elevated ALT levels. No differences in CIMT and arterial wall stiffness were observed between those without and with steatosis and those with steatosis plus elevated ALT levels [CIMT = 0.47 (±0.06), 0.48 (±0.06) and 0.48 (±0.07) mm, respectively; stiffness = 2.78 (±0.50), 3.00 (±0.81), and 2.90 (±0.78), respectively]. Steatosis and ALT were not correlated to CIMT (r = -0.02 and -0.14, respectively) or arterial wall stiffness (r = 0.13 and -0.11, respectively). In this study, no relationship between NAFLD and early atherosclerotic changes in children was observed. An atherogenic effect of steatohepatitis (NASH) on pediatric age and long-term atherogenic consequences of simple steatosis cannot be excluded based on this study.

Research paper thumbnail of New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond

Journal of hepatology, 2015

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholang... more Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors ...

Research paper thumbnail of Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity

Obesity (Silver Spring, Md.), Jan 9, 2015

Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for ca... more Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for cardiovascular disease in adults. It has not been established whether NAFLD is related to early atherosclerotic changes in children. In a cross-sectional study, 78 non diabetic, non smoking children with severe obesity were evaluated for NAFLD. Proton magnetic resonance spectroscopy was used to detect liver steatosis and serum ALT was used as a surrogate marker for steatohepatitis. Carotid intima-media thickness (CIMT) and arterial wall stiffness were measured using ultrasound. Steatosis was present in 41 (53%) of subjects. Of these children, 26 out of 41 (63%) had elevated ALT levels. No differences in CIMT and arterial wall stiffness were observed between those without and with steatosis and those with steatosis plus elevated ALT levels [CIMT = 0.47 (±0.06), 0.48 (±0.06) and 0.48 (±0.07) mm, respectively; stiffness = 2.78 (±0.50), 3.00 (±0.81), and 2.90 (±0.78), respectively]. Steatosis ...

Research paper thumbnail of New developments in the antiviral treatment of hepatitis C

Vox sanguinis, 2009

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular ... more Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is endemic in most parts of the world, with an estimated 170 million people infected worldwide and 3-4 million new cases each year. HCV-related end-stage liver disease is now the main indication for liver transplantation in the USA and Western Europe. Unfortunately, no vaccine or immunoglobulin is available to prevent HCV infection. Currently, HCV treatment consists of the combined administration of pegylated interferon and ribavirin for a period of 24-48 weeks, resulting in complete viral eradication in 40-80% of patients, depending on genotype, viral load and patient characteristics. This therapy is often accompanied with side-effects that affect compliance and reduce treatment outcomes. Recently, reliable in vitro culture systems have been developed which accelerated antiviral therapy research. Many new specifically targeted antiviral therapies for hepatitis C (STAT-C) ...

Research paper thumbnail of Determination of ammonia in cerebrospinal fluid using the indophenol direct method

Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid

We have determined ammonia in cerebrospinal fluid (CSF) with the indophenol direct method. The re... more We have determined ammonia in cerebrospinal fluid (CSF) with the indophenol direct method. The results were compared with an enzymatic method. The method is very simple, and precision (coefficient of variation 1.6%) and linearity (r = 0.9999, p < 0.001) of the method are excellent. The recoveries of the method are very good (within-sample recovery: range 88-93, median 93%; between-sample recovery: 88-93, median 91%). In a population of 23 neurological patients not suffering from liver disease, the reference values ranged from 8 to 26, median 18 microM. Males and females did not differ (p = 0.5). The values obtained with the indophenol method were equal to the enzymatic method (range 9-28, median 18 microM, p = 0.6). On storage in the deep freeze (-20 degrees C), there was no change in CSF ammonia concentration for at least 1 mo. When stored at 4 degrees C (refrigerator), ammonia determinations have to be performed within 2 d. CSF storage at room temperature results in artificiall...

Research paper thumbnail of Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells

Liver International, 2001

Moshage H. Involvement of reactive oxygen species and nitric oxide Stefania Saccomanno 1 , radica... more Moshage H. Involvement of reactive oxygen species and nitric oxide Stefania Saccomanno 1 , radicals in activation and proliferation of rat hepatic stellate cells. Abstract: Background /Aims: Reactive oxygen species (ROS) induce HSCs ide (NO) represents a reactive molecule that reacts with ROS, yielding Gastroenterology and Hepatology, University peroxynitrite. We thus verified the effect of NO on ROS-induced HSCs Hospital Groningen, The Netherlands

Research paper thumbnail of Mechanisms of Bile Formation: An Introduction

Molecular Pathogenesis of Cholestasis, 2004

Research paper thumbnail of Monitoring of Total and Regional Liver Function after SIRT

Frontiers in oncology, 2014

Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepato... more Selective internal radiation therapy (SIRT) is a promising treatment modality for advanced hepatocellular carcinoma or metastatic liver cancer. SIRT is usually well tolerated. However, in most patients, SIRT will result in a (temporary) decreased liver function. Occasionally patients develop radioembolization-induced liver disease (REILD). In case of a high tumor burden of the liver, it could be beneficial to perform SIRT in two sessions enabling the primary untreated liver segments to guarantee liver function until function in the treated segments has recovered or functional hypertrophy has occurred. Clinically used liver function tests provide evidence of only one of the many liver functions, though all of them lack the possibility of assessment of segmental (regional) liver function. Hepatobiliary scintigraphy (HBS) has been validated as a tool to assess total and regional liver function in liver surgery. It is also used to assess segmental liver function before and after portal ...

Research paper thumbnail of Bile acid receptors as targets for drug development

Nature Reviews Gastroenterology & Hepatology, 2013

| The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled... more | The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.