Van Mil Lab at UMC Utrecht
Molecular and translational metabolism
The van Mil group aims to better understand the underlying cause of human metabolic diseases and associated cancer development and to spur and contribute to the development of improved diagnostics as well as improved therapeutic approaches.
The deciphering of metabolic pathways was one of the first major breakthroughs in modern molecular research in life sciences, detailed on the well-known Boehringer wall-charts. The interest in metabolism has been high ever since, and knowledge on biochemical pathways has developed hand in hand with the discovery of hundreds of inborn errors of metabolism. In the last decades, with the rise of acquired metabolic/inflammatory diseases such as diabetes, metabolic syndrome, non-alcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and necrotizing enterocolitis, the interest in molecular metabolism has become even more important. Especially, since there is a high prevalence of developing cancer due to derailed metabolism. The analysis of molecular metabolism has therefore become an intricate part in our quests to understand the cause and consequences of these diseases and associated cancers and to find new treatment modalities.
Research
Selective targeting of FXR isoforms as treatment of non-alcoholic steatohepatitis.
The Farnesoid X Receptor (FXR, NR1H4) is a member of the nuclear receptor (NR) superfamily. Upon binding bile acids, FXR is activated and initiates transcription of a pleithora of genes involved in fatty acid, amino acid and glucose metabolism, and inflammation. FXR is expressed as four isoforms, FXR α1 to α4, which differ in their AF-1 domain (α1/2 vs α3/4) and in a four amino acid insertion in the hinge region. All isoforms activate transcription via binding an inverted hexamer repeat spaced by one nucleotide (IR1) in the DNA. We have recently shown that FXRα2/4, the non-MYTG containing isoforms, additionally activate transcription from an ER2 motif, an everted repeat spaced by two nucleotides, which comprises 90% of all DNA binding by FXR. We have revealed isoform selective functions in pyruvate transport and lipid de novo lipogenesis. We therefore are currently investigating whether selective targeting of the non-MYTG containing isoforms as a treatment for NASH.
FXR/NR1H4 gene and isoforms
Hepatic encephalopathy is prevented by treatment with rifaximin, but how?
The poorly absorbed antibiotic rifaximin - a Pregnane X Receptor (PXR) agonist - prevents recurrent hepatic encephalopathy (HE). Although the pathophysiology of HE is only partly unravelled, ammonia accumulation, systemic inflammation and oxidative stress appear to play a central role. Ammonia is detoxified by formation of glutamine and urea. Due to its poor absorption, rifaximin is considered to exert beneficial effect on HE by acting on the gut microbiome, thereby decreasing bacterial ammonia production. Direct effects of rifaximin on intestinal epithelium have barely been studied. We are currently investigating the hypothesis that rifaximin may be effective in HE by strengthening the human intestinal epithelial detoxification capacity.
Effects of dietary metabolites on intestinal epithelial development
Necrotizing enterocolitis (NEC) is one of the most lethal diseases of the gut affecting 5-7% of preterm babies. It is characterized by diarrhea, blood in the stools and food intolerance mainly caused by inflammation of the intestine. Even though the exact etiology is unknown and probably multifactorial, it appears that the inflammation is caused by exposure of the underdeveloped intestine to nutrition and the microbiota. Strikingly, breast milk reduces the risk of developing NEC in preterm babies by 6-10x fold in contrast to formula-fed infants. We currently investigate the effect of nutrition on gut epithelial development, in order to better understand the onset of the disease and to spur new treatment options.
Metabolomic fingerprinting of disease
For inflammatory bowel disease, to classify type and severity of the disease state, invasive endoscopy is needed. Using machine learning approaches, we aim to pinpoint differences in metabolomic signature between IBD patients and controles in bloodspots, both by per-metabolite statistical analysis and building a predictive model to separate different patient groups. Subsequently, we set out to find annotations for these molecular markers indicating an existing connection of the disease with the underlying causes and consequences. Ultimately, we aim to provide predictive models for non-invasive diagnosis and monitoring of the disease.
News
Dec. 4th, 2022
Koos de Wit, Anna Muhka and Saskia van Mil published an article in Liver International about the direct effects of Rifaximin on the intesitnal epithelium. The article is titled Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids and we conclude that:
Rifaximin stimulates intracellular nitrogen detofixication
Rifaximin is excreted apically (into the intestinal lumen) via ABCB1
Graphical abstract of the article. Published open-access!
Nov. 10th, 2022
Judith de Jong presented at the Nuclear Receptor Research Network (NRRN) meeting in Utrecht.
Suzanne van der Veen won a prize for the best poster at NRRN.
Sept 14th, 2022
Koos de Wit presented his research with an oral presentation during the President Select session at the Digestive Disease Days of the Netherlands Society of Gastroenterology and won the best abstract prize.
Sept 13th, 2022
Suzanne van der Veen presented her poster “RXR is not an obligatory dimerization partner of FXR” at the EMBO 2022 Workshop meeting “On a 20/20 vision of the future of nuclear receptors”.
July 17th, 2022
Professor Saskia van Mil was interviewed by the Dutch television news service RTL Nieuws regarding a Nature Metabolism study about “Food-seeking behavior is triggered by skin ultraviolet exposure in males”. The full interview can be found here: Mannen hebben meer trek dan vrouwen als de zon schijnt
July 8th, 2022
Professor Saskia van Mil gave her inaugural lecture titled
“Mustard Bile after the meal”
on Friday July 8th at 4:15 p.m.
You can watch the inaugural lecture via http://youtu.be/WXOG_pwfEec
June 22nd, 2022
Saskia van Mil and Koos de Wit participated in The International Liver Congress 2022, organised by EASL.
Saskia was in the organising committee and Koos de Wit presented a poster.
June 12th-13th, 2022
Judith de Jong presented at the Dutch Translation Metabolism Conference as selected speaker. Title of her presentation was “The effect of acetate on intestinal maturation in prevention of necrotizing enterocolitis”
June 1st, 2022
The van Mil group and Kalkhoven group held their yearly “Metabowling” event. Congratulations to dr. Bob van Eijkeren on being the ultimate Metabowler champion.
Jan. 3rd, 2022
Miranda van Triest started as research technician, as successor of Suzanne van der Veen, who now started as PhD student in the van Mil lab
Dec. 17th, 2021
Interview with Saskia van Mil by the Netherlands Association for the Study of the Liver (NASL), presented in “LEVER”.
https://www.hepatologie.org/lever_magazine/lever-december-2021/
Dec. 1st, 2021
Jamie van der Vaart started her Master internship and will be working on the role of acetylation of FXR in the ER-2 mediated target gene transcription in the context of NAFLD.
Nov. 15th, 2021
Maureen van Rooijen started her Bachelor internship and in the lab she will focus on the interaction between FXR and beta-catenin.
July 17th, 2021
We congratulate Maria Rodriquez Colman, who receives a TKI HealthHolland grant entitled: The Anti-Cancer Diet: Dissecting the molecular mechanisms to support therapeutic strategies. Saskia van Mil, Boudewijn Burgering and Danica Bajic (DSM) are coapplicants. See https://rodriguezcolmanlab.org/contact/. With this new project we will extend our collaboration with DSM and expand our studies on the effects of nutrition on proliferation and differentiation of the intestinal epithelium.
July 1st, 2021
Saskia starts as Head of the Center for Molecular Medicine.
June 28th, 2021
Saskia van Mil and Koos de Wit participated in the International Liver Congress 2021, organized by EASL. The congress took place from 23 to 26 June, and its main motto was beating liver disease together.
Apr. 15th, 2021
Abdelrahman El-Gammal started as a PhD candidate in the van Mil group. He will investigate the roles of the Farnesoid X Receptor (FXR) isoforms in the progression of NASH and how to selectively increase the expression of specific isoforms of FXR.
Jan. 1st, 2021
Monique Appelman has started as a postdoc in the van Mil group. She will investigate alternative splicing of FXR in NAFLD.
Feb. 20th, 2020
Saskia van Mil receives VICI grant of 1,5mEuro to study ‘Selective targeting of FXR isoforms as treatment of non-alcoholic steatohepatitis’
May 1st, 2020
Anna Mukha has started as a postdoc in the van Mil group. She will be investigating the effects of different FXR isoforms on liver metabolism in vivo.
Group members
Saskia van Mil
PhD — S.W.C.vanMil@umcutrecht.nl
Saskia van Mil (PhD) is Professor of Molecular and Translational Metabolism at the University Medical Center Utrecht, and Director of the Center for Molecular Medicine (www.cmmutrecht.eu). She is a member of the governing board and scientific committee of the European Association for the Study of the Liver (www.easl.eu).
She received her PhD from the University of Utrecht in 2004, on the topic of genetic disorders of pediatric cholestasis. As a post-doc at Imperial College London, United Kingdom, she studied the role of the bile salt sensor farnesoid X receptor (FXR) in intrahepatic cholestasis of pregnancy.
Since then, she has been intrigued by the versatility in molecular mechanisms of transcription by the nuclear receptor FXR and its therapeutic potential. Having received funding from the Netherlands’ Organisation of Scientific Research (Veni, Vidi, Vici), European Commission, Dutch Digestive Disease Foundation and DSM, her group studies the molecular and translational aspects of energy metabolism in the liver and the intestine. Amongst other projects, her group studies the molecular mechanisms of FXR function in metabolic disorders (e.g. NASH) and disorders of intestinal integrity (e.g. IBD).
Miranda van Triest
M.H.vanTriest@umcutrecht.nl
Miranda is the research technician in the van Mil Lab. After completing her bachelor’s degree at Saxion University of Applied Sciences Miranda started as a research technician in the group of Prof. dr. Hans Bos (Utrecht University, Physiological Chemistry), studying the regulation and function of Ras-like small GTPases. Subsequently she joined the group of Prof. dr. Boudewijn Burgering investigating the role and regulation of FOXO transcription factors. She enjoys to start working as a research technician in the van Mil lab in January 2022.
Anna Mukha
A.Mukha@umcutrecht.nl
Anna did her bachelor’s and master’s studies at the National University of Kyiv-Mohyla Academy (Ukraine), and worked in the Institute of Molecular Biology and Genetics (Ukraine) for several years after receiving her master’s diploma. After that Anna got her doctoral degree from the Medical Faculty of TU Dresden (Germany), where she studied metabolic alterations in prostate cancer and neuroblastoma in context of radiation oncology. From May 2020 she works as a Postdoc in the van Mil lab, studying FXR isoforms in NAFLD and cancer. Her research interests include metabolism, cancer progression and therapy resistance.
Monique Appelman
M.D.Appelman-2@umcutrecht.nl
Monique is a postdoctoral fellow in the van Mil lab. She studied Biomedical Sciencies in Amsterdam in the direction of Biochemistry and Metabolic Disorders. Subsequently she did her PhD in the van de Graaf group at the Tytgat Institute in Amsterdam. There she investigated the regulation of the bile acid transporter NTCP. After her PhD, she continued in the liver metabolism field as she is currently also working on this topic. In her project in the van Mil lab she focusses on the nuclear receptor FXR and tries to unravel how FXR isoform expression is regulated in NAFLD.
Judith de Jong
J.C.W.deJong-28@umcutrecht.nl
Judith is a PhD student in the van Mil lab. She completed the master Nutrition and Health with the specialization Molecular Nutrition at Wageningen University. During this master, she performed internships at Danone Nutriticia Research as well as in the Klip Lab, part of the Cell Biology program at the SickKids Hospital in Toronto, Canada. These internships inspired her to pursue a PhD related to nutrition and cell biology. In the van Mil lab, she is investigating in which way dietary metabolites have an influence on intestinal epithelial development. This gives insights into the fundamental biology behind intestinal development and the preventive potential of nutrition in intestinal diseases occurring in early-life.
Koos de Wit
K.deWit-5@umcutrecht.nl
Koos is a PhD candidate in the van Mil lab. He works as a MD in Amsterdam UMC location AMC at the department of Gastroenterology and Hepatology and his PhD focusses on patients with liver cirrhosis. In particular prevention of complications of this end-stage liver disease like portal hypertension, variceal bleeding and ascites. He is the coordinating investigator of the PEARL trial (Prevention of post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose) and sub-investigator of the LIVERHOPE_EFFICACY study (Rifaximin and Simvastatin to prevent complications of cirrhosis). In his laboratory studies at the van Mil lab he studies the effects of rifaximin on the Pregnane X Receptor (PXR) in human small intestinal organoids and human hepatic organoids in order to generate insights in the beneficial effects of this drug.
Joanna Wolthuis
J.C.Wolthuis@umcutrecht.nl
Joanna is a PhD candidate working on direct infusion mass spectrometry metabolomics research. Coming from a Biomedical Sciences BSc and subsequently the Molecular and Cellular Life Sciences MSc, she discovered the joys of (bio)informatics and pursued a PhD in that area. In her work, she focusses on development of an R/R Shiny application called MetaboShiny, which facilitates these analyses. She currently applies MetaboShiny to swine, chicken and human gut health datasets to elucidate mechanisms causing gut inflammation.
Suzanne van der Veen
S.W.vanderVeen-8@umcutrecht.nl
Suzanne joined the Van Mil lab in 2018 as a research technician. She obtained her bachelor’s degree at Saxion University of Applied Science. During her bachelor, she performed research internships in pediatric oncology and genetics, which raised her interest in the molecular mechanisms of diseases. After working for more than 3 years in the Van Mil Lab, she started her PhD in 2022 to investigate the role of Farnesoid X Receptor (FXR) isoforms in the liver. In her project, she will work on specifically increasing FXRalpha2 expression through alternative splicing and the mechanisms of the transcriptional activity of FXR.
Abdelrahman El-Gammal
A.G.A.Elgammal@umcutrecht.nl
Abdelrahman is a PhD student in the van Mil lab. He did his bachelor’s degree in Biotechnology at Cairo University, Egypt followed by a master’s degree in Molecular Medicine at Uppsala University, Sweden. His master’s thesis project was carried out in the group of Prof. Magnus Ingelman-Sundberg in the Physiology and Pharmacology Department at the Karolinksa Institute, Sweden. In his project, he investigated the mechanism of action of GLP-1 receptor agonists in NASH treatment using a 3D liver spheroid NASH model. In the van Mil lab, he is investigating the roles of the Farnesoid X Receptor (FXR) isoforms in the progression of NASH and how to selectively increase the expression of specific isoforms of FXR.
Dana Meije
Dana is a research intern in the van Mil lab. She is a master student Biomedical Sciences at the University of Amsterdam and discovered her keen interest in research into liver metabolism during her previous internship at the Tytgat Institute (Amsterdam UMC). Therefore, she decided to further expand her experience and knowledge in this field, during her internship in the van Mil lab under the supervision of Suzanne van der Veen. The project she will be working on, mainly focusses on the regulation of alternative splicing of FXR, with the ultimate aim of specifically increasing FXRa2 expression.
Former group members
Jamie van der Vaart
Maureen van Rooijen
Laurine van Gijn
Stefania Magnusdottir
Noortje IJssennagger
Kristel van Rooijen
Jose Miguel Ramos Pittol
Ellen Willemsen
Ingrid Bijsmans
Alexandra Milona
Raffaella Gadaleta
Publications
Most recent
Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids
Koos de Wit, Ulrich Beuers, Anna Mukha, Edwin Stigter, M. Can Gulersonmez, Jose M. Ramos Pittol, Sabine Middendorp, R. Bart Takkenberg and Saskia W. C. van Mil. Liver International; 2022
Protein Condensation in the Nuclear Receptor Family; Implications for Transcriptional Output
Monique D. Appelman, Elle E. Hollaar, Jurian Schuijers & Saskia W. C. van Mil. Nuclear Receptors in Human Health and Disease pp 243–253
Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders
Monique D. Appelman, Suzanne W. van der Veen and Saskia W. C. van Mil. Frontiers in Endocrinology; 2021 Sep 27;12:729828
Ablation of liver Fxr results in an increased colonic mucus barrier in mice
Noortje Ijssennagger, Kristel van Rooijen, Stefanía Magnúsdóttir, José M Ramos Pittol, Ellen Willemsen, Marcel de Zoete, Matthijs Baars, Paul Stege, Carolina Colliva, Roberto Pellicciari, Sameh A Youssef, Alain de Bruin, Yvonne Vercoulen, Folkert Kuipers, Saskia W C van Mil. JHEP reports 2021 Aug 4;3(5):100344
Judith C.W. de Jong, Noortje Ijssennagger, Saskia W.C. van Mil. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2021.
Anna Mukha, Eric Kalkhoven, Saskia W.C. van Mil. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2021
FXR Isoforms Control Different Metabolic Functions in Liver Cells via Binding to Specific DNA Motifs
Jose Miguel Ramos Pittol, Alexandra Milona, Imogen Morris, Ellen C.L. Willemsen, Suzanne W. van der Veen, Eric Kalkhoven, Saskia W.C. van Mil. Gastroenterology 2020
Steroidogenic control of liver metabolism through a nuclear receptor-network. Milona A, Massafra V, Vos H, Naik J, Artigas N, Paterson HAB, Bijsmans ITGW, Willemsen ECL, Ramos Pittol JM, Miguel-Aliaga I, Bosma P, Burgering BMT, Williamson C, Vernia S, Dhillo WS, van Mil SWC, Owen BM.Mol Metab. 2019 Dec;30:221-229. doi: 10.1016/j.molmet.2019.09.007.
[Non-alcoholic fatty liver disease; a full-bodied epidemic]. Tushuizen ME, Holleboom AG, Koot BGP, Blokzijl H, van Mil SWC, Koek GH.Ned Tijdschr Geneeskd. 2020 Feb 27;164:D4096.
Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool. Passeri D, Carotti A, Pittol JMR, Ciaccioli G, Pellicciari R, van Mil SWC, Gioiello A.Medchemcomm. 2019 Jun 24;10(8):1412-1419. doi: 10.1039/c9md00264b.
Identification of FDA-approved drugs targeting the Farnesoid X Receptor. van de Wiel SMW, Bijsmans ITGW, van Mil SWC, van de Graaf SFJ.Sci Rep. 2019 Feb 18;9(1):2193. doi: 10.1038/s41598-019-38668-7
Progress and challenges of selective Farnesoid X Receptor modulation. Massafra V, Pellicciari R, Gioiello A, van Mil SWC.Pharmacol Ther. 2018 Nov;191:162-177. doi: 10.1016/j.pharmthera.2018.06.009.
Profiling of 3696 Nuclear Receptor-Coregulator Interactions: A Resource for Biological and Clinical Discovery. Broekema MF, Hollman DAA, Koppen A, van den Ham HJ, Melchers D, Pijnenburg D, Ruijtenbeek R, van Mil SWC, Houtman R, Kalkhoven E.Endocrinology. 2018 Jun 1;159(6):2397-2407. doi: 10.1210/en.2018-00149.
Protein fermentation in the gut; implications for intestinal dysfunction in humans, pigs, and poultry. Gilbert MS, Ijssennagger N, Kies AK, van Mil SWC.Am J Physiol Gastrointest Liver Physiol. 2018 Aug 1;315(2):G159-G170. doi: 10.1152/ajpgi.00319.2017
Farnesoid X receptor: A "homeostat" for hepatic nutrient metabolism. Massafra V, van Mil SWC.Biochim Biophys Acta Mol Basis Dis. 2018 Jan;1864(1):45-59. doi: 10.1016/j.bbadis.2017.10.003.