Publications by authors named "Frank G Schaap"

83 Publications

Hepatic Steatosis Contributes to the Development of Muscle Atrophy Inter-Organ Crosstalk.

Front Endocrinol (Lausanne) 2021 11;12:733625. Epub 2021 Oct 11.

Department of Human Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, Netherlands.

Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200-µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomics analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like growth factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.
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http://dx.doi.org/10.3389/fendo.2021.733625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542925PMC
October 2021

Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration.

Hepatol Commun 2021 Aug 5;5(8):1400-1411. Epub 2021 May 5.

Department of Surgery NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Maastricht The Netherlands.

The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated ( < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver ( < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward ( < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor () was markedly up-regulated following surgery ( < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [], signal transducer and activator of transcription 3 [], and ) were up-regulated following surgery and were positively correlated with expression  < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low and high Na+/Taurocholate cotransporting polypeptide () expression in the remnant liver coupled with higher liver bile salt content ( < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR ( < 0.05). : Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.
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http://dx.doi.org/10.1002/hep4.1728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369949PMC
August 2021

Chyme Reinfusion Restores the Regulatory Bile Salt-FGF19 Axis in Patients With Intestinal Failure.

Hepatology 2021 Nov 26;74(5):2670-2683. Epub 2021 Aug 26.

Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.

Background And Aims: Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt-FGF19 axis.

Approach And Results: Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7-α-hydroxy-4-cholesten-3-one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up-regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course.

Conclusions: CR in patients with IF-TDE restored bile salt-FGF19 signaling and improved gut-liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.
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http://dx.doi.org/10.1002/hep.32017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596508PMC
November 2021

Postprandial rise of essential amino acids is impaired during critical illness and unrelated to small-intestinal function.

JPEN J Parenter Enteral Nutr 2021 Mar 5. Epub 2021 Mar 5.

Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Background: Postprandial rise of plasma essential amino acids (EAAs) determines the anabolic effect of dietary protein. Disturbed gastrointestinal function could impair the anabolic response in critically ill patients. Aim was to investigate the postprandial EAA response in critically ill patients and its relation to small-intestinal function.

Methods: Twenty-one mechanically ventilated patients and 9 healthy controls received a bolus containing 100 ml of a formula feed (Ensure) and 2 g of 3-O-Methyl-d-glucose (3-OMG) via postpyloric feeding tube. Fasting and postprandial plasma concentrations of EAAs, 3-OMG, total bile salts, and the gut-released hormone fibroblast growth factor 19 (FGF19) were measured over a 4-hour period. Changes over time and between groups were assessed with linear mixed-effects analysis. Early (0-60 minutes) and total postprandial responses are summarized as the incremental area under the curve (iAUC).

Results: At baseline, fasting EAA levels were similar in both groups: 1181 (1055-1276) vs 1150 (1065-1334) μmol·L-1, P = .87. The early postprandial rise in EAA was not apparent in critically ill patients compared with healthy controls (iAUC , -4858 [-6859 to 2886] vs 5406 [3099-16,853] µmol·L ·60 minutes; P = .039). Impaired EAA response did not correlate with impaired 3-OMG response (Spearman ρ 0.32, P = .09). There was a limited increase in total bile salts but no relevant FGF19 response in either group.

Conclusion: Postprandial rise of EAA is blunted in critically ill patients and unrelated to glucose absorption measured with 3-OMG. Future studies should aim to delineate governing mechanisms of macronutrient malabsorption.
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http://dx.doi.org/10.1002/jpen.2103DOI Listing
March 2021

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.

Biomolecules 2021 02 10;11(2). Epub 2021 Feb 10.

Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.
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http://dx.doi.org/10.3390/biom11020260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916678PMC
February 2021

The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice.

Horm Metab Res 2020 Dec 1;52(12):869-876. Epub 2020 Dec 1.

Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.
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http://dx.doi.org/10.1055/a-1301-2378DOI Listing
December 2020

Parenteral nutrition impairs plasma bile acid and gut hormone responses to mixed meal testing in lean healthy men.

Clin Nutr 2021 03 14;40(3):1013-1021. Epub 2020 Jul 14.

Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background & Aims: To investigate the acute effects of intravenous vs enteral meal administration on circulating bile acid and gut hormone responses.

Methods: In a randomized crossover design, we compared the effects of duodenal (via a nasoduodenal tube) vs parenteral (intravenous) administration over 180 min of identical mixed meals on circulating bile acid and gut hormone concentrations in eight healthy lean men. We analysed the bile acid and gut hormone responses in two periods: the intraprandial period from time point (T) 0 until T180 during meal administration and the postprandial period from T180 until T360, after discontinuation of meal administration.

Results: Intravenous meal administration decreased the intraprandial (AUC (μmol/L∗min) duodenal 1469 ± 284 vs intravenous 240 ± 39, p < 0.01) and postprandial bile acid response (985 ± 240 vs 223 ± 5, p < 0.05) and was accompanied by decreased gut hormone responses including glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon-like peptide 2 and fibroblast growth factor 19. Furthermore, intravenous meal administration elicited greater glucose concentrations, but similar insulin concentrations compared to enteral administration.

Conclusions: Compared to enteral administration, parenteral nutrition results in lower postprandial bile acid and gut hormone responses in healthy lean men. This was accompanied by higher glucose concentrations in the face of similar insulin concentrations exposing a clear incretin effect of enteral mixed meal administration. The alterations in bile acid homeostasis were apparent after only one intravenous meal.
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http://dx.doi.org/10.1016/j.clnu.2020.06.032DOI Listing
March 2021

Gut Microbes Take It to the Next Level? First Insights Into Farnesoid X Receptor Agonists of Microbial Origin.

Hepatology 2020 10;72(4):1483-1485

Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.

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http://dx.doi.org/10.1002/hep.31455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702049PMC
October 2020

Effect of wheat bran derived prebiotic supplementation on gastrointestinal transit, gut microbiota, and metabolic health: a randomized controlled trial in healthy adults with a slow gut transit.

Gut Microbes 2020 11 25;12(1):1704141. Epub 2020 Jan 25.

Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+ , Maastricht, The Netherlands.

Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of . NCT02491125.
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http://dx.doi.org/10.1080/19490976.2019.1704141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524158PMC
November 2020

Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses.

Am J Physiol Endocrinol Metab 2019 09 25;317(3):E494-E502. Epub 2019 Jun 25.

Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, The Netherlands.

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In : we tested 4-h mixed meal after an overnight fast and a 40-h fast. In , we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In , 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In , administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.
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http://dx.doi.org/10.1152/ajpendo.00534.2018DOI Listing
September 2019

Low circulating concentrations of citrulline and FGF19 predict chronic cholestasis and poor survival in adult patients with chronic intestinal failure: development of a Model for End-Stage Intestinal Failure (MESIF risk score).

Am J Clin Nutr 2019 06;109(6):1620-1629

Department of Surgery, Maastricht, Netherlands.

Background: Patients with chronic intestinal failure (CIF) often develop cholestatic liver injury, which may lead to liver failure and need for organ transplantation.

Objectives: The aim of this study was to investigate whether citrulline (CIT) and the enterokine fibroblast growth factor 19 (FGF19) are associated with chronic cholestasis and survival in adult CIF patients, and to develop a risk score to predict their survival.

Methods: We studied 135 adult CIF patients on intravenous supplementation (>3 mo). Associations of plasma CIT and FGF19 with chronic cholestasis and survival were estimated by logistic and Cox regression models. A predictive risk score was developed and validated internally.

Results: Patients with chronic cholestasis (17%) had a reduced 5-y survival rate compared with patients without chronic cholestasis (38% and 62%, respectively). In multivariable analysis, low FGF19, low CIT, and female sex were associated with chronic cholestasis. Patients with low rather than high CIT or FGF19 also had reduced 5-y survival rates (29% compared with 69%; 54% compared with 66%, respectively). Risk factors identified in multivariable analysis of survival were low FGF19 (HR: 3.4), low CIT (HR: 3.3), and number of intravenous infusions per week (HR: 1.4). These 3 predictors were incorporated in a risk model of survival termed Model for End-Stage Intestinal Failure (MESIF) (C-statistic 0.78). The 5-y survival rates for patients with MESIF scores of 0 to <20 (n = 47), 20-40 (n = 75), and >40 (n = 13) were 80%, 58%, and 14%, respectively.

Conclusions: CIT and FGF19 predict chronic cholestasis and survival in this cohort of adult CIF patients, and the derived MESIF score is associated with their survival. Pending external validation, the MESIF score may help to identify patients for closer clinical monitoring or earlier referral to intestinal transplantation centers.
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http://dx.doi.org/10.1093/ajcn/nqz036DOI Listing
June 2019

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.

Hepatology 2019 07 5;70(1):308-318. Epub 2019 Jun 5.

Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.

Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
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http://dx.doi.org/10.1002/hep.30629DOI Listing
July 2019

Ophthalmic acid as a read-out for hepatic glutathione metabolism in humans.

J Clin Transl Res 2018 Jul 25;3(Suppl 2):366-374. Epub 2018 Mar 25.

Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.

Background And Aim: Animal studies indicated that systemic ophthalmic acid (OPH) is a biomarker for hepatic glutathione (GSH) homeostasis, an important determinant of liver function. We aimed to clarify whether OPH levels can be used as a read-out for hepatic GSH homeostasis after paracetamol (APAP) challenges during pylorus-preserving pancreaticoduodenectomy (PPPD) or partial hepatectomy (PH).

Methods: Nineteen patients undergoing PPPD (n=7, control group) or PH (n=12) were included. APAP (1000 mg) was administered intravenously before resection (first challenge), and six and twelve hours later, with sequential blood sampling during this period. Arterial, hepatic and portal venous blood samples and liver biopsies were taken on three occasions during the first APAP challenge. Plasma and hepatic OPH and GSH levels were quantified, and venous-arterial differences were calculated to study hepatic release.

Results: Systemic GSH levels decreased during the course of the APAP challenge in both surgical groups, without notable change in OPH levels. Hepatic GSH and OPH content was not affected within ˜3 hours after administration of the first APAP dose in patients undergoing PPPD or PH. In this period, net release of OPH by the liver was observed only in patients undergoing PPPD.

Conclusion: The drop in circulating GSH levels following APAP administrations, did not result in an increase in plasma OPH in both patients with an intact liver and in those undergoing liver resection. Hepatic content of GSH and OPH was not affected during the first APAP dose. It is uncertain whether hepatic GSH homeostasis was sufficiently challenged in the present study.

Relevance For Patients: In the present study, plasma OPH seemed not useful as a marker for GSH depletion because APAP administration during liver surgery did not lead to (immediate) GSH depletion or increased OPH levels. Based on stable levels of hepatic GSH, OPH and thiyl radicals during surgery, standard APAP administration seems to be safe in a postoperative care program with regards to GSH homeostasis in this specific population. However, no general statements can be made on the basis of the current experiment, since GSH homeostasis and susceptibility to xenobiotic toxicity are influenced by several metabolic and genetic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412618PMC
July 2018

The cholic acid extension study in Zellweger spectrum disorders: Results and implications for therapy.

J Inherit Metab Dis 2019 03 21;42(2):303-312. Epub 2019 Feb 21.

Department of Pediatric Neurology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Introduction: Currently, no therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. In a previous study, we showed that oral cholic acid (CA) treatment can suppress bile acid synthesis in ZSD patients and, thereby, decrease plasma levels of toxic C -bile acid intermediates, one of the biochemical abnormalities in these patients. However, no effect on clinically relevant outcome measures could be observed after 9 months of CA treatment. It was noted that, in patients with advanced liver disease, caution is needed because of possible hepatotoxicity.

Methods: An extension study of the previously conducted pretest-posttest design study was conducted including 17 patients with a ZSD. All patients received oral CA for an additional period of 12 months, encompassing a total of 21 months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21 months of treatment.

Results: Bile acid synthesis was still suppressed after 21 months of CA treatment, accompanied with reduced levels of C -bile acid intermediates in plasma. These levels significantly increased again after discontinuation of CA. No significant changes were found in liver tests, liver elasticity, coagulation parameters, fat-soluble vitamin levels or body weight.

Conclusions: Although CA treatment did lead to reduced levels of toxic C -bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21 months of treatment. We discuss the implications for CA therapy in ZSD based on these results.
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http://dx.doi.org/10.1002/jimd.12042DOI Listing
March 2019

Duodenal-jejunal lining increases postprandial unconjugated bile acid responses and disrupts the bile acid-FXR-FGF19 axis in humans.

Metabolism 2019 04 15;93:25-32. Epub 2019 Jan 15.

Amsterdam UMC, University of Amsterdam, Department of Endocrinology and Metabolism, Amsterdam Gastroenterology & Metabolism Research Institute, Meibergdreef 9, Amsterdam, the Netherlands. Electronic address:

Background And Aims: Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement.

Methods: We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement.

Results: Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandial plasma courses were unaffected.

Conclusions: DJBL placement leads to profound increases in unconjugated bile acid levels after 6 months, similar to the effects of bariatric surgery. The temporal dissociation between the changes in bile acids, GLP-1 and FGF19 and other gut hormone responses warrant caution about the beneficial role of bile acids after DJBL placement. This observational uncontrolled study emphasizes the need for future controlled studies.
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http://dx.doi.org/10.1016/j.metabol.2018.12.009DOI Listing
April 2019

Effect of Plasmapheresis on Cholestatic Pruritus and Autotaxin Activity During Pregnancy.

Hepatology 2019 06 14;69(6):2707-2710. Epub 2019 Feb 14.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1002/hep.30496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593664PMC
June 2019

FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis.

Sci Rep 2018 11 8;8(1):16529. Epub 2018 Nov 8.

Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.
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http://dx.doi.org/10.1038/s41598-018-33070-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224438PMC
November 2018

Cross-Species Molecular Imaging of Bile Salts and Lipids in Liver: Identification of Molecular Structural Markers in Health and Disease.

Anal Chem 2018 10 4;90(20):11835-11846. Epub 2018 Oct 4.

Maastricht Multimodal Molecular Imaging Institute (M4I) , University of Maastricht , Universiteitssingel 50 , 6229 ER Maastricht , The Netherlands.

The liver is the primary organ involved in handling of bile salts, a class of amphipathic molecules with signaling activities as well as desired and detrimental detergent actions. To allow in-depth investigation of functions of bile salts in healthy and diseased liver, the spatial distribution of bile salt species within the liver needs to be studied. Therefore, the aim of our study was to determine hepatic bile salt distribution and identify specific lipid markers that define the structural elements of the liver. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to monitor the spatial distribution of bile salts and lipids in liver sections of rat, dog, and patients with unaffected and cholestatic parenchyma. MALDI-MSI in negative ion mode showed the local presence of a variety of bile salts, predominantly taurine-conjugates, as localized patches of varying sizes (representing the bile ducts) throughout the liver tissue. Specific molecular markers were identified for the connective tissue (phosphatidic acids, e.g., [PA (18:0_18:1)-H]), the liver parenchyma (phosphatidylinositols, e.g., [PI (18:0_20:4)-H]), and the bile ducts (hydroxylated-sulfatides, e.g., [ST-OH (18:1_24:0)-H]). One of these sulfatides (at m/ z 906.6339) was found to be uniquely localized in a thin lining on the inside of the bile duct, colocalized with cytokeratins, and encased luminal bile salts. A similar distribution of the aforementioned sulfatide was observed, albeit in constricted ductular structures, in the liver of a patient with a mild clinical phenotype of primary sclerosing cholangitis (PSC). In contrast, sulfatides were virtually absent in the liver of patients with PSC and a severe clinical phenotype, with (atypical) cholanoids (e.g., the bile alcohol 5-cyprinolsulfate) abundant in the extra-ductular space and glyco(cheno)deoxycholic acid-3-sulfate localized to fibrotic connective tissue. The latter two molecular species were able to discriminate between healthy liver tissue ( n = 3) and tissue from PSC patients with a severe clinical phenotype ( n = 3). In conclusion, the distinct structural elements of the mammalian liver are characterized by specific classes of lipids. We propose that (hydroxylated-)sulfatides are specific molecular markers of the bile duct.
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http://dx.doi.org/10.1021/acs.analchem.8b01378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193250PMC
October 2018

Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study.

PLoS One 2017 6;12(12):e0188475. Epub 2017 Dec 6.

Department of Internal and Vascular Medicine, Academic Medical Center-University of Amsterdam, Amsterdam, the Netherlands.

Objective: Environmental factors driving the development of type 1 diabetes (T1D) are still largely unknown. Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset. However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking.

Research Design And Methods: We included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI. Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured.

Results: Oral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC. Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes. Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA. Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA.

Conclusions: We conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels. Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188475PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718513PMC
December 2017

FXR agonism protects against liver injury in a rat model of intestinal failure-associated liver disease.

J Clin Transl Res 2018 Jan 15;3(3):318-327. Epub 2017 Oct 15.

Department of Surgery, Maastricht University Medical Center, Maastricht University, NUTRIM School of Nutrition and Translational Research in Me-tabolism, Maastricht, the Netherlands.

Background: Intestinal failure-associated liver disease (IFALD) is a clinical challenge. The pathophysiol-ogy is multifactorial and remains poorly understood. Disturbed recirculation of bile salts, due to loss of bile via an enterocutaneous fistula, is considered a major contributing factor. We hypothesize that impaired signaling via the bile salt receptor FXR underlies the development of IFALD. The aim of this study was to investigate whether activation of FXR improves liver homeostasis during chronic loss of bile in rats.

Methods: To study consequences of chronic loss of bile, rats underwent external biliary drainage (EBD) or sham surgery for seven days, and the prophylactic potential of the FXR agonist INT-747 was assessed.

Results: EBD for 7 days resulted in liver test abnormalities and histological liver damage. Expression of the intestinal FXR target gene was undetectable after EBD, and this was accompanied by an anticipated increase in hepatic expression, indicating increased bile salt synthesis. Treatment with INT-747 improved serum biochemistry, reduced loss of bile fluid in drained rats and prevented development of drainage-associated histological liver injury.

Conclusions: EBD results in extensive hepatobiliary injury and cholestasis. These data suggest that FXR activation might be a novel therapy in preventing liver dysfunction in patients with intestinal failure.

Relevance For Patients: This study demonstrates that chronic loss of bile causes liver injury in rats. Abro-gated recycling of bile salts impairing of enterohepatic bile salt/FXR signaling underlies these pathological changes, as administration of FXR agonist INT747 prevents biliary drainage-induced liver damage. Phar-macological activation of FXR might be a therapeutic strategy to treat disorders accompanied by a per-turbed enterohepatic circulation such as intestinal failure-associated liver disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426251PMC
January 2018

Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition.

Cell Metab 2017 Oct;26(4):611-619.e6

Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Top Institute of Food and Nutrition, 6700 AN Wageningen, the Netherlands; Department of Internal Medicine, VUMC, Free University, Amsterdam, the Netherlands; Wallenberg Laboratory, Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden. Electronic address:

The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We therefore studied the effect of lean donor (allogenic) versus own (autologous) fecal microbiota transplantation (FMT) to male recipients with the metabolic syndrome. Whereas we did not observe metabolic changes at 18 weeks after FMT, insulin sensitivity at 6 weeks after allogenic FMT was significantly improved, accompanied by altered microbiota composition. We also observed changes in plasma metabolites such as γ-aminobutyric acid and show that metabolic response upon allogenic FMT (defined as improved insulin sensitivity 6 weeks after FMT) is dependent on decreased fecal microbial diversity at baseline. In conclusion, the beneficial effects of lean donor FMT on glucose metabolism are associated with changes in intestinal microbiota and plasma metabolites and can be predicted based on baseline fecal microbiota composition.
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http://dx.doi.org/10.1016/j.cmet.2017.09.008DOI Listing
October 2017

Chronic elevation of plasma fibroblast growth factor 19 in long-term farnesoid X receptor agonist therapy, a happy marriage or cause for oncological concern?

Hepatology 2018 02 26;67(2):782-784. Epub 2017 Dec 26.

Department of Surgery, Maastricht University NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University, Maastricht, The Netherlands.

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http://dx.doi.org/10.1002/hep.29511DOI Listing
February 2018

Interactions between bile salts, gut microbiota, and hepatic innate immunity.

Immunol Rev 2017 Sep;279(1):23-35

Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.
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http://dx.doi.org/10.1111/imr.12579DOI Listing
September 2017

Validation of gene expression profiles from cholestatic hepatotoxicants in vitro against human in vivo cholestasis.

Toxicol In Vitro 2017 Oct 1;44:322-329. Epub 2017 Aug 1.

Department of Toxicogenomics, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands; Netherlands Toxicogenomics Centre, Maastricht, The Netherlands. Electronic address:

Drug-induced liver injury remains the most common cause of acute liver failure and a frequently indicated reason for withdrawal of drugs. For the purpose of evaluating the relevance of liver cell models for assessing hepatotoxic risks in intact humans, we here aimed to benchmark 'omics-derived mechanistic data from three in vitro models for parenchymal liver function, intended for the investigation of drug-induced cholestasis, against 'omics data from cholestatic patients. Transcriptomic changes in HepG2 cells, primary mouse hepatocytes and primary human hepatocytes exposed to known cholestatic compounds were analyzed using microarrays. Some of the differentially expressed genes in HepG2 cells were also differentially expressed into the same direction in human cholestasis. The overlap between drug-induced transcriptomic responses in primary mouse hepatocytes and primary human hepatocytes appeared limited and no genes overlapping with in vivo cholestasis were found. Thereupon, a pathway for drug-induced cholestasis was used to map the drug-induced transcriptomic modifications involved in bile salt homeostasis. Indications of an adaptive response to prevent and reduce intracellular bile salt accumulation were observed in vivo as well as in the in vitro liver models. Furthermore, drug-specific changes were found, which may be indicative for their cholestatic properties. Furthermore, connectivity mapping was applied in order to investigate the predictive value of the in vitro models for in vivo cholestasis. This analysis resulted in a positive connection score for most compounds, which may indicate that for identifying cholestatic compounds the focus should be on gene expression signatures rather than on differentially expressed genes.
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http://dx.doi.org/10.1016/j.tiv.2017.07.024DOI Listing
October 2017

Cathepsin D regulates lipid metabolism in murine steatohepatitis.

Sci Rep 2017 06 14;7(1):3494. Epub 2017 Jun 14.

Departments of Molecular Genetics, Human Biology and Surgery, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229 ER, Maastricht, The Netherlands.

Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism.

Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.
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http://dx.doi.org/10.1038/s41598-017-03796-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471235PMC
June 2017

Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.

J Hepatol 2017 06 2;66(6):1214-1222. Epub 2017 Feb 2.

K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Dept. of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC).

Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100).

Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival.

Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.

Lay Summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis.
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http://dx.doi.org/10.1016/j.jhep.2017.01.019DOI Listing
June 2017

Parenteral nutrition dysregulates bile salt homeostasis in a rat model of parenteral nutrition-associated liver disease.

Clin Nutr 2017 10 24;36(5):1403-1410. Epub 2016 Sep 24.

Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Institute for Liver and Digestive Health, University College London, London, United Kingdom. Electronic address:

Background & Aims: Parenteral nutrition (PN), a lifesaving therapy in patients with intestinal failure, has been associated with hepatobiliary complications including steatosis, cholestasis and fibrosis, collectively known as parenteral nutrition-associated liver disease (PNALD). To date, the pathogenesis of PNALD is poorly understood and therapeutic options are limited. Impaired bile salt homeostasis has been proposed to contribute PNALD. The objective of this study was to establish a PNALD model in rats and to evaluate the effects of continuous parenteral nutrition (PN) on bile salt homeostasis.

Methods: Rats received either PN via the jugular vein or received normal diet for 3, 7 or 14 days. Serum biochemistry, hepatic triglycerides, circulating bile salts and C4, IL-6 and TNF-alpha, and lipogenic and bile salt homeostatic gene expression in liver and ileum were assessed.

Results: PN increased hepatic triglycerides already after 3 days of administration, and resulted in conjugated bilirubin elevation after 7 or more days. This indicates PN-induced steatosis and impaired canalicular secretion of bilirubin, the latter which is in line with reduced hepatic expression of Mrp2 mRNA. There was no histological evidence for liver inflammation after PN administration, and circulating levels of pro-inflammatory cytokines IL-6 and TNF-α, were comparable in all groups. Hepatic expression of Fxr mRNA was decreased after 7 days of PN, without apparent effect on expression of Fxr targets Bsep and Shp. Nonetheless, Cyp7a1 expression was reduced after 7 days of PN, indicative for lowered bile salt synthesis. Circulating levels of C4 (marker of bile salt synthesis) were also decreased after 3, 7 and 14 days of PN. Levels of circulating bile salts were not affected by PN.

Conclusions: This study showed that PN in rats caused early mild steatosis and cholestasis, while hepatic and systemic inflammation were not present. The onset of these abnormalities was associated with alterations in bile salt synthesis and transport. This animal model serves as an experimental model to further investigate the pathogenesis of PNALD inflicted by steatosis and cholestasis.
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http://dx.doi.org/10.1016/j.clnu.2016.09.012DOI Listing
October 2017

The portal-drained viscera release fibroblast growth factor 19 in humans.

Physiol Rep 2016 12;4(24)

Department of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University, Maastricht, The Netherlands.

Fibroblast growth factor 19 (FGF19) is an ileum-derived endrocrine factor that is produced in response to transepithelial bile salt flux. FGF19 represses bile salt synthesis in the liver. Despite the general assumption that FGF19 signals to the liver via portal blood, no human data are available to support this notion. The aim was to study portal FGF19 levels, and determined bile salt and FGF19 fluxes across visceral organs in humans. Bile salt and FGF19 levels were assessed in arterial, portal, and hepatic venous blood collected from fasted patients who underwent partial liver resection for colorectal liver metastases (n = 30). Fluxes across the portal-drained viscera (PDV), liver, and splanchnic area were calculated. Portal bile salt levels (7.8 [5.0-12.4] μmol/L) were higher than levels in arterial (2.7 [1.7-5.5] μmol/L, P < 0.0001) and hepatic venous blood (3.4 [2.5-6.5] μmol/L, P < 0.0001). Bile salts released by the PDV (+1.2 [+0.7-+2.0] mmol kg h, P < 0.0001) were largely taken up by the liver (-1.0 [-1.8 to -0.4] mmol kg h, P < 0.0001). Portal levels of FGF19 (161 ± 78 pg/mL) were higher than arterial levels (135 ± 65 pg/mL, P = 0.046). A net release of FGF19 by the PDV (+4.0 [+2.1 to +9.9] ng kg h, P < 0.0001) was calculated. There was no significant flux of FGF19 across the liver (-0.2 [-3.7 to +7.4] ng kg h, P = 0.93). In conclusion, FGF19 levels in human portal blood are higher than in arterial blood. FGF19 is released by the portal-drained viscera under fasted steady state conditions.
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http://dx.doi.org/10.14814/phy2.13037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210390PMC
December 2016

Integrative "-Omics" Analysis in Primary Human Hepatocytes Unravels Persistent Mechanisms of Cyclosporine A-Induced Cholestasis.

Chem Res Toxicol 2016 12 2;29(12):2164-2174. Epub 2016 Dec 2.

Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University , P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

Cyclosporine A (CsA) is an undecapeptide with strong immunosuppressant activities and is used a lot after organ transplantation. Furthermore, it may induce cholestasis in the liver. In general, the drug-induced cholestasis (DIC) pathway includes genes involved in the uptake, synthesis, conjugation, and secretion of bile acids. However, whether CsA-induced changes in the cholestasis pathway in vitro are persistent for repeated dose toxicity has not yet been investigated. To explore this, primary human hepatocytes (PHH) were exposed to a subcytotoxic dose of 30 μM CsA daily for 3 and 5 days. To investigate the persistence of induced changes upon terminating CsA exposure after 5 days, a subset of PHH was subjected to a washout period (WO-period) of 3 days. Multiple -omics analyses, comprising whole genome analysis of DNA methylation, gene expression, and microRNA expression, were performed. The CsA-treatment resulted after 3 and 5 days, respectively, in 476 and 20 differentially methylated genes (DMGs), 1353 and 1481 differentially expressed genes (DEGs), and in 22 and 29 differentially expressed microRNAs (DE-miRs). Cholestasis-related pathways appeared induced during CsA-treatment. Interestingly, 828 persistent DEGs and 6 persistent DE-miRs but no persistent DMGs were found after the WO-period. These persistent DEGs and DE-miRs showed concordance for 22 genes. Furthermore, 29 persistent DEGs changed into the same direction as observed in livers from cholestasis patients. None of those 29 DEGs which among others relate to oxidative stress and lipid metabolism are yet present in the DIC pathway or cholestasis adverse outcome pathway (AOP) thus presenting novel findings. In summary, we have demonstrated for the first time a persistent impact of repeated dose administration of CsA on genes and microRNAs related to DIC in the gold standard human liver in vitro model with PHH.
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http://dx.doi.org/10.1021/acs.chemrestox.6b00337DOI Listing
December 2016

The ascending pathophysiology of cholestatic liver disease.

Hepatology 2017 02;65(2):722-738

Research Network of Liver Systems Medicine, Freiburg, Germany.

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).
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http://dx.doi.org/10.1002/hep.28965DOI Listing
February 2017
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