Project

Back to overview

Regulation and Role of ABCA1-mediated Cholesterol Transfer in the Human Placenta in Health and Disease: Protecting the Fetal Environment and/or Maintaining Placental Endocrine Function?

English title Regulation and Role of ABCA1-mediated Cholesterol Transfer in the Human Placenta in Health and Disease: Protecting the Fetal Environment and/or Maintaining Placental Endocrine Function?
Applicant Albrecht Christiane
Number 149958
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physiology : other topics
Start/End 01.05.2014 - 30.04.2018
Approved amount 337'000.00
Show all

All Disciplines (5)

Discipline
Physiology : other topics
Gynaecology
Biochemistry
Cellular Biology, Cytology
Molecular Biology

Keywords (8)

pre-eclampsia; placenta; transport ; pregnancy ; aldosterone; cholesterol; steroidogenesis; human placenta perfusion

Lay Summary (German)

Lead
Das Membranprotein ABCA1 spielt eine wichtige Rolle im zellulären Cholesterintransport. Unsere bisherigen humanmedizinischen Studien haben gezeigt, dass ABCA1 offensichtlich für eine gesunde Entwicklung der Plazenta und damit für das Wohlergehen des Fetus unabdingbar ist. Die Funktion von ABCA1 bzw. die zugrundeliegenden molekularen Grundlagen sind jedoch immer noch weitgehend ungeklärt. In dem vorliegenden Forschungsprojekt sollen nunmehr die molekularen Wirkungsmechanismen und hormonellen Regulationsprozesse von ABCA1 in der humanen Plazenta intensiv untersucht werden und dessen Bedeutung in spezifischen Schwangerschaftserkrankungen geklärt werden.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Das Membranprotein ABCA1 ist im ersten Trimester der Schwangerschaft essentiell für den Transfer von Cholesterin zwischen der Mutter und dem Fetus. Bisherige Studien lassen allerdings darauf schliessen, dass ABCA1 noch weitere wichtige Funktionen in der Plazenta einnimmt, und bei bestimmten Schwangerschaftserkrankungen wie der "Prä-eklampsie"dysreguliert ist. Um die genaue Rolle dieses Membranproteins in der gesunden wie auch erkrankten Plazenta herauszufinden, werden dessen Kontrollmechanismen, Regulationsfaktoren sowie Signalübertragungswege mittels molekular- und zellbiologischen Methoden untersucht. Insbesondere soll auch die Bedeutung dieses Proteins für die Aufrechterhaltung der für die Schwangerschaft essentiellen Hormone geklärt werden. Ferner wird die wichtige Frage untersucht, ob ABCA1 in weiteren Schwangerschaftserkrankungen eine Rolle spielt bzw. inwieweit auch andere Lipid-/Cholesterintransporter in der Entstehung oder Pathologie dieser Schwangerschaftserkrankungen involviert sind.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Die Erkenntnisse dieser Studien könnten sowohl für die Diagnose wie auch für die Entwicklung therapeutischer Interventionsmöglichkeiten bei diversen Schwangerschaftserkrankungen von grossem Interesse sein.

Direct link to Lay Summary Last update: 19.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia
Fuenzalida Bárbara, Cantin Claudette, Kallol Sampada, Carvajal Lorena, Pastén Valentina, Contreras-Duarte Susana, Albrecht Christiane, Gutierrez Jaime, Leiva Andrea (2020), Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia, in Scientific Reports, 10(1), 1-16.
Materno-fetal cholesterol transport during pregnancy
Kallol Sampada, Albrecht Christiane (2020), Materno-fetal cholesterol transport during pregnancy, in Biochemical Society Transactions, 1-12.
IFPA meeting 2018 workshop report II: Abnormally invasive placenta; inflammation and infection; preeclampsia; gestational trophoblastic disease and drug delivery
Albrecht C., Chamley L., Charnock-Jones D.S., Collins S., Fujiwara H., Golos T., Grayo S., Hannan N., Harris L., Ichizuka K., Illsley N.P., Iwashita M., Kallol S., Al-Khan A., Lash G., Nagamatsu T., Nakashima A., Niimi K., Nomoto M., Redman C., Saito S., Tanimura K., Tomi M., Usui H., Vatish M., Wolfe B., Yamamoto E., O'Tierney-Ginn P. (2019), IFPA meeting 2018 workshop report II: Abnormally invasive placenta; inflammation and infection; preeclampsia; gestational trophoblastic disease and drug delivery, 84, 9-13, Elsevier, Amsterdam 84, 9-13.
Placental secretion of apolipoprotein A1 and E: the anti-atherogenic impact of the placenta
Melhem H., Kallol S., Huang X., Lüthi M., Ontsouka C.E., Keogh A., Stroka D., Thormann W., Schneider H., Albrecht C. (2019), Placental secretion of apolipoprotein A1 and E: the anti-atherogenic impact of the placenta, in Scientific Reports, 9(1), 1-12.
Placental miR-340 mediates vulnerability to activity based anorexia in mice
Schroeder Mariana, Jakovcevski Mira, Polacheck Tamar, Drori Yonat, Luoni Alessia, Röh Simone, Zaugg Jonas, Ben-Dor Shifra, Albrecht Christiane, Chen Alon (2018), Placental miR-340 mediates vulnerability to activity based anorexia in mice, in Nature Communications, 9(1), 1596-1596.
Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia
Huang Xiao, Anderle Pascale, Hostettler Lu, Baumann Marc U., Surbek Daniel V., Ontsouka Edgar C., Albrecht Christiane (2018), Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia, in BMC Genomics, 19(1), 173-173.
Comparative expression patterns of selected membrane transporters in differentiated BeWo and human primary trophoblast cells
Kallol S., Moser-Haessig R., Ontsouka C.E., Albrecht C. (2018), Comparative expression patterns of selected membrane transporters in differentiated BeWo and human primary trophoblast cells, in Placenta, 72-73, 48-52, Elsevier, Amsterdam 72-73, 48-52.
IFPA meeting 2016 workshop report I: Genomic communication, bioinformatics, trophoblast biology and transport systems
Albrecht Christiane, Baker Julie C., Blundell Cassidy, Chavez Shawn L., Carbone Lucia, Chamley Larry, Hannibal Roberta L., Illsley Nick, Kurre Peter, Laurent Louise C., McKenzie Charles, Morales-Prieto Diana, Pantham Priyadarshini, Paquette Alison, Powell Katie, Price Nathan, Rao Balaji M., Sadovsky Yoel, Salomon Carlos, Tuteja Geetu, Wilson Samantha, O'Tierney-Ginn P.F. (2017), IFPA meeting 2016 workshop report I: Genomic communication, bioinformatics, trophoblast biology and transport systems, in Placenta, 60, S5-S9.
Effect of placental cell differentiation on materno-fetal nutrient transport
Sampada Kallol (2017), Effect of placental cell differentiation on materno-fetal nutrient transport, in IFPA 2017, Elsevier, UK.
IFPA meeting 2015 workshop report III: nanomedicine applications and exosome biology, xenobiotics and endocrine disruptors and pregnancy, and lipid
Albrecht C., Caniggia I., Clifton V., Göhner C., Harris L., Hemmings D., Jawerbaum A., Johnstone E., Jones H., Keelan J., Lewis R., Mitchell M., Murthi P., Powell T., Saffery R., Smith R., Vaillancourt C., Wadsack C., Salomon C. (2016), IFPA meeting 2015 workshop report III: nanomedicine applications and exosome biology, xenobiotics and endocrine disruptors and pregnancy, and lipid, in Placenta, 48, S12-S16.
Differential expression of selected placental membrane transporters during syncytium formation in vitro
Sampada Kallol (2016), Differential expression of selected placental membrane transporters during syncytium formation in vitro, in IFPA 2016, Elsevier, UK.
Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport.
Huang Xiao, Lüthi Michael, Ontsouka Edgar C, Kallol Sampada, Baumann Marc U, Surbek Daniel V, Albrecht Christiane (2016), Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport., in Molecular human reproduction, 22(6), 442-56.
Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation.
Eisele Nicole, Albrecht Christiane, Mistry Hiten D, Dick Bernhard, Baumann Marc, Surbek Daniel, Currie Gemma, Delles Christian, Mohaupt Markus G, Escher Geneviève, Gennari-Moser Carine (2016), Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation., in Placenta, 40, 18-24.
Importance of Cholesterol and Cholesterol Transporters in the Placental Trophoblast during Pregnancy.
Arjun Jain, Christiane Albrecht (2015), Importance of Cholesterol and Cholesterol Transporters in the Placental Trophoblast during Pregnancy., in Asim K. Duttaroy Sanjay Basak (ed.), CRC Press, USA, 129-144.
Identification of important placental nutrient transporters in intrauterine growth restriction and preeclampsia using various strategies
Xiao Huang (2015), Identification of important placental nutrient transporters in intrauterine growth restriction and preeclampsia using various strategies, in IFPA 2015, Elsevier, UK.
Impaired placental thiamine transport in human pregnancy diseases
Xiao Huang (2015), Impaired placental thiamine transport in human pregnancy diseases, in IFPA 2015, Elsevier, UK.
Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response.
Jain Arjun, Schneider Henning, Aliyev Eldar, Soydemir Fatimah, Baumann Marc, Surbek Daniel, Hediger Matthias, Brownbill Paul, Albrecht Christiane (2014), Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response., in Laboratory investigation; a journal of technical methods and pathology, 94(8), 873-80.

Collaboration

Group / person Country
Types of collaboration
Prof. Paul Brownbill, University of Manchester, Manchester, UK Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Michael Grössl, Dept. of Nephrology and Hypertension, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Dr. Ruedi Moser, Lindenhofgruppe Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Hiten Mistry, University of Nottingham Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. Meike Körner, Inst. of Pathology, University of Bern & Pathologie Länggasse, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Mariana Schröder, Max Planck Institute of Psychiatry, Munich Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Christian Wadsack, University of Graz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Jahrestagung der Deutschen Gesellschaft für Nephrologie Talk given at a conference Kultivierte Trophoblasten sind Salz-sensitiv und exprimieren Na+ und Cl-Transporter differenziell in Plazenta und Nieren von Salz-belasteten Ratten. 14.09.2017 Mannheim, Germany Mohaupt Markus; Albrecht Christiane; Kallol Sampada Arvindrao;
International Society for the Study of Hypertension in Pregnancy (ISSHP) European Congress Talk given at a conference Osmolality responses by TonEBP and SMIT in placental trophoblast cell lines 06.09.2017 Berlin, Germany Albrecht Christiane; Kallol Sampada Arvindrao; Mohaupt Markus;
International Federation of Placenta Associations Meeting Poster Effect of placental cell differentiation on materno-fetal nutrient transport 30.08.2017 Manchester, Great Britain and Northern Ireland Kallol Sampada Arvindrao; Albrecht Christiane; Surbek Daniel;
BioMedical Transporters 2017 Poster Placental cell differentiation affects expression and function of materno-fetal nutrient transporters. 06.08.2017 Lausanne, Switzerland Surbek Daniel; Kallol Sampada Arvindrao; Albrecht Christiane;
11. Jahrestagung der Mitteldeutschen Gesellschaft für Frauenheilkunde und Geburtshilfe Talk given at a conference Kultivierte Trophoblasten sind Salz-sensitiv und NaCl-Transporter sind in Plazenta und Niere von Salz-exponierten Ratten differenziell reguliert. 19.05.2017 Leipzig, Germany Kallol Sampada Arvindrao; Albrecht Christiane; Mohaupt Markus;
Day of Clinical Research Poster Differential expression of selected placental membrane transporters during syncytium formation in vitro. 02.11.2016 Bern, Switzerland Kallol Sampada Arvindrao; Albrecht Christiane; Mohaupt Markus; Surbek Daniel;
International Federation of Placenta Associations Meeting Poster GLUT1-down-regulation leads to a “premature senesce” in preeclamptic sycytiotrophoblasts 13.09.2016 Portland, United States of America Surbek Daniel; Albrecht Christiane;
International Federation of Placenta Associations Meeting Talk given at a conference Primary trophoblast Transwell model mimicking the function of chorionic villi. 13.09.2016 Portland, United States of America Kallol Sampada Arvindrao; Surbek Daniel; Albrecht Christiane; Mohaupt Markus;
International Federation of Placenta Associations Meeting Poster Differential expression of selected placental membrane transporters during syncytium formation in vitro. 13.09.2016 Portland, United States of America Kallol Sampada Arvindrao; Albrecht Christiane; Surbek Daniel;
9th European Placenta Perfusion Workshop Talk given at a conference In-house production of a highly efficient oxygenator 14.06.2016 Graz, Austria Venkateswaran Nithya; Albrecht Christiane;
Gordon Research Conference “Membrane Transport Proteins” Talk given at a conference Placental membrane transporters: bottleneck between mother and fetus? 12.06.2016 Lucca (Barga), Italy Albrecht Christiane;
International Federation of Placenta Associations Meeting Poster Identification of important placental nutrient transporters in intrauterine growth restriction and preeclampsia using various strategies. 08.09.2015 Brisbane, Australia Albrecht Christiane; Surbek Daniel;
Biomedical Transporters 2015 Poster Novel approaches to decipher the importance of membrane transporters in pregnancy diseases. 09.08.2015 Lugano, Switzerland Albrecht Christiane; Surbek Daniel; Kallol Sampada Arvindrao;
Biomedical Transporters 2015 Poster Differential expression of selected placental membrane transporters during syncytium formation in vitro 09.08.2015 Lugano, Switzerland Surbek Daniel; Kallol Sampada Arvindrao; Albrecht Christiane; Venkateswaran Nithya;
8th European Placenta Perfusion Workshop Talk given at a conference The multicannular approach – an update. 23.06.2015 Bern, Switzerland Albrecht Christiane; Venkateswaran Nithya;
8th European Placenta Perfusion Workshop Talk given at a conference Practical and technical improvements of the dual placenta perfusion system. 23.06.2015 Bern, Switzerland Albrecht Christiane; Venkateswaran Nithya;
International Federation of Placenta Associations Meeting Poster Materno-fetal nutrient transfer across primary human trophoblast layer 09.09.2014 Paris, France Surbek Daniel; Albrecht Christiane;
International Federation of Placenta Associations Meeting Poster Placental Glucose Transporter (GLUT)-1 regulation in pre-eclampsia. 09.09.2014 Paris, France Albrecht Christiane; Surbek Daniel;
7th European Placenta Perfusion Workshop Talk given at a conference First experiences with a multicannulae device for the perfusion of the intervillous space. 24.06.2014 Jena, Germany Albrecht Christiane; Venkateswaran Nithya; Kallol Sampada Arvindrao; Surbek Daniel;


Self-organised

Title Date Place
8th European Placenta Perfusion Workshop 23.06.2015 Bern, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Nacht der Forschung der Universität Bern Talk 16.09.2017 Bern, Switzerland Albrecht Christiane; Kallol Sampada Arvindrao; Berchtold Regina;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Ein Wunder im Bauch German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
119984 The role of ABCA1 in the human placenta: physiological relevance and implication in diseases of pregnancy 01.11.2008 Project funding (Div. I-III)
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)
119984 The role of ABCA1 in the human placenta: physiological relevance and implication in diseases of pregnancy 01.11.2008 Project funding (Div. I-III)

Abstract

The ATP-binding cassette transporter A1 (ABCA1) mediates the transport of cholesterol, phospholipids and other lipophilic compounds across cellular membranes. Hereby it is implicated in the physiology of cellular cholesterol homeostasis and reverse cholesterol transport as well as in hereditary lipid disorders and atherosclerosis. Lately, evidence evolved on the role of ABCA1 in normal and pathological pregnancies at the placenta level. Studies in ABCA1 null mice revealed catastrophic effects of ABCA1 deficiency in the placenta including intrauterine growth restriction and increased rates of neonatal death. Moreover, we recently have demonstrated differential ABCA1 mRNA and protein expression in placentas obtained from patients with pre-eclampsia, a clinically severe gestational disease with lifelong consequences for both mother and child, where ABCA1 was specifically downregulated in syncytiotrophoblasts and fetal endothelial cells, i.e. particularly at the sites of materno-fetal cholesterol exchange. However, the mode of action as well as the molecular mechanisms underlying and controlling ABCA1 function in the human placenta in health and disease are only poorly understood. Novel data from our group suggested that manipulating ABCA1 function in placental primary cells has severe effects on the placental production of progesterone, a steroid hormone essential for the maintenance of pregnancy. Moreover, preliminary studies from our laboratory indicated that aldosterone, a hormone recently acknowledged as of major importance for the uteroplacental unit, showed a novel formerly unrecognized action on ABCA1. Aldosterone downregulated ABCA1 function in the frequently used RAW 264.7 macrophage model but not in placental syncytiotrohoblasts despite functional mineralocorticoid receptors being expressed in both cell types. This suggests a differential regulation of ABCA1 protecting the placenta from this adverse effect of aldosterone and provides a potential key to understand aldosterone-induced vasculopathy and accelerated atherosclerosis.To elucidate the relevance of ABCA1 in physiology and pathophysiology of the human placenta and to identify underlying control mechanisms of ABCA1 action in this organ, our research team will perform a rigorous examination of the regulatory factors and signaling pathways, and to explore the cause and relevance of reduced ABCA1 expression in pre-eclampsia. Our central hypotheses are that I) ABCA1 function in the placenta is maintained despite high aldosterone levels indicating differential regulation to preserve transplacental cholesterol transport and that II) ABCA1 activity during pregnancy has to be tightly controlled to maintain cholesterol-dependent steroid hormone synthesis within the placenta. To test these assumptions we will a) investigate the role and mode of action of aldosterone in the regulation of ABCA1 expression and function in a variety of relevant placenta-derived primary cells, macrophages and control cells, b) determine the impact of ABCA1 in the maintenance of steroid hormone synthesis/metabolism in the placenta, c) investigate the control mechanisms of ABCA1 expression and function in healthy placentas, and its dysregulation in pre-eclampsia. In all of the above mentioned investigations we will assure to delineate the role of ABCA1 from other lipid transporters and sterol responsive genes.The results of these studies will contribute to a better understanding of the mode(s) of action of ABCA1 in the human placenta and the reasons and pathophysiological consequences associated with dysregulated ABCA1 function. Our investigations will reveal whether and by which mechanism ABCA1 contributes to normal placental development, and will provide novel insights into the regulatory mechanisms which control ABCA1 action in the healthy and compromised placenta. The identification of ABCA1, or other candidate genes investigated in our studies, as potential key players in pre-eclampsia might generate novel options for diagnosis or therapeutic intervention in this severe and clinically relevant disease. Furthermore, this research is likely to explain some features of vasculopathy and accelerated atherosclerosis in high aldosterone states in non-pregnant individuals and to identify candidate protective pathways.
-