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Role of CYP27A1 expression in reverse cholesterol transport and atherosclerosis in an atherosclerotic mouse model

English title Role of CYP27A1 expression in reverse cholesterol transport and atherosclerosis in an atherosclerotic mouse model
Applicant Escher Geneviève
Number 122133
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.12.2008 - 30.11.2011
Approved amount 250'000.00
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Keywords (14)

CYP27A1; atherosclerosis; in vivo reverse cholesterol transport; macrophages; CYP27A1(+/-)/ApoE(-/-) mice; western diet; sterol 27-hydroxylase; reverse cholesterol transport; urinary steroids; adenovirus; reverse cholesterol transport; atherosclerosis; sterol 27-hydroxylase; cholesterol efflux

Lay Summary (English)

Lead
Lay summary

The development of an atherosclerotic plaque is a decade lasting event. Its progression is dependant on gender, genetic and environmental factors. Accumulation of cholesterol in the vessel wall is one of the key elements in the pathogenesis of atherosclerosis. Therefore, it is reasonable to hypothesize that enhancing pathways of intracellular cholesterol removal is a promising target for the prevention and treatment of this disease. In a previously published study, I have shown that over-expression of the sterol 27-hydroxylase CYP27A1, one of the enzymes accounting for the first step of reverse cholesterol transport (RCT), enhances cholesterol efflux in a mice macrophage cell line. Furthermore, in vivo RCT in mice was increased when this macrophage cell line was first transfected with CYP27A1.

The aim of my present research is to define the relevance of CYP27A1 in reverse cholesterol transport in vivo and its contribution to the formation/dissolution of the atherosclerotic plaque in an atherosclerotic mouse model.

I propose, first, to analyse in detail the phenotype of CYP27A1(+/+)/ApoE(-/-), CYP27A1+/-)/ApoE(-/-) and CYP27A1(-/-)/ApoE(-/-) mice I have obtained by crossing CYP27A1(-/-) mice with ApoE/(-/-), the relevant model of mice atherosclerosis. Second, the impact of a high cholesterol diet will be assessed on urinary steroids and the development of atherosclerotic plaques. Third, I will analyse the impact of macrophage specific expression of CYP27A1 on the cholesterol release in vivo by harvesting peritoneal macrophages from these mice. Following ex vivo labelling with 3H-cholesterol, these macrophages will be re-injected in recipient mice and RCT will be assessed by quantifying the appearance of labelled cholesterol in plasma, liver and faeces. Fourth, in order to distinguish between the effect of CPY27A1 and other genes of RCT, a specific depletion of Kupffer cells will be performed by the administration of 25 mg/kg liposomal clodronate 24h before the in vivo RCT assay. Finally, in an attempt to reconstitute CYP27A1 expression, adenovirus expressing CYP27A1 (AdCYP27A1) will be injected in CYP27A1(+/-)/ApoE(-/-) and the effect on the atherosclerotic phenotype will be analysed.

Thus, the present project will help to clarify the role of CYP27A1 expression in macrophages and its anti-atherosclerotic role in mice. If my hypothesis is correct, future studies focussing on the up-regulation of CPY27A1 will follow with the ultimate goal to enhance RCT in humans as a novel alternative for the treatment of atherosclerosis.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study.
Ackermann D Pruijm M Ponte B Guessous I Ehret G Escher G Dick B Al-Alwan H Vuistiner P Pacc (2016), CYP17A1 Enzyme Activity Is Linked to Ambulatory Blood Pressure in a Family-Based Population Study., in Am J Hypertens, 4, 484-493.
H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K(+) restriction.
Walter C Tanfous MB Igoudjil K Salhi A Escher G Crambert G. (2016), H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K(+) restriction., in Pflugers Arch., 468(10), 1673-1683.
Maternal Serum Lipid, Estradiol, and Progesterone Levels in Pregnancy, and the Impact of Placental and Hepatic Pathologies.
Pecks U Rath W Kleine-Eggebrecht N Maass N Voigt F Goecke TW Mohaupt MG Escher G (2016), Maternal Serum Lipid, Estradiol, and Progesterone Levels in Pregnancy, and the Impact of Placental and Hepatic Pathologies., in Geburtshilfe Frauenheilkd, 76(7), 799-808.
Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation.
Eisele N Albrecht C Mistry HD Dick B Baumann M Surbek D Currie G Delles C Mohaupt MG Escher (2016), Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation., in Placenta, 40, 18-24.
ENaC activity in collecting ducts modulates NCC in cirrhotic mice.
Mordasini D Loffing-Cueni D Loffing J Beatrice R Maillard MP Hummler E Burnier M Escher G Vo (2015), ENaC activity in collecting ducts modulates NCC in cirrhotic mice., in Pflugers Arch., 467(12), 2529-2539.
Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum.
Mistry HD Eisele N Escher G Dick B Surbek D Delles C Currie G Schlembach D Mohaupt MG Genna (2015), Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum., in Reprod Biol Endocrinol, 13(101), 1-13.
Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses.
Pecks U Mohaupt MG Hütten MC Maass N Rath W Escher G (2014), Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses., in Biochim Biophys Acta, 1841(2), 251-258.
Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE-knockout mice.
Zurkinden L Solcà C Vögeli IA Vogt B Ackermann D Erickson SK Frey FJ Sviridov D Escher G. (2014), Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE-knockout mice., in FASEB J, 3, 1198-1209.
Normotensive blood pressure in pregnancy: the role of salt and aldosterone
Gennari-Moser C Escher G Kramer S Dick B Eisele N Baumann M Raio L Frey FJ Surbek D Mohaupt (2014), Normotensive blood pressure in pregnancy: the role of salt and aldosterone, in Hypertension, 63(2), 362-368.
Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo. J Endocrinol.
Vögeli I Jung HH Dick B Erickson SK Escher R Funder JW Frey FJ Escher G (2013), Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo. J Endocrinol., in J Endocrinol, 219(2), 119-129.
Response to "Are aldosterone levels inappropriately low in preeclampsia"?
Gennari-Moser C Khankin EV Escher G Burkhard F Frey BM Karumanchi SA Frey FJ Mohaupt MG. (2013), Response to "Are aldosterone levels inappropriately low in preeclampsia"?, in Hypertension, 62(5), e40.
Vascular endothelial growth factor-A and aldosterone: relevance to normal pregnancy and preeclampsia. Hypertension
Gennari-Moser C Khankin EV Escher G Burkhard F Frey BM Karumanchi SA Frey FJ Mohaupt MG (2013), Vascular endothelial growth factor-A and aldosterone: relevance to normal pregnancy and preeclampsia. Hypertension, in Hypertension, 61(5), 1111-1117.
High salt intake down-regulates colonic mineralocorticoid receptors, epithelial sodium channels and 11β-hydroxysteroid dehydrogenase type 2
Lienhard D Lauterburg M Escher G Frey FJ Frey BM (2012), High salt intake down-regulates colonic mineralocorticoid receptors, epithelial sodium channels and 11β-hydroxysteroid dehydrogenase type 2, in PLoS One, 7(5), e37898.
Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats.
• Lauterburg M Escher G Dick B Ackermann D Frey FJ. (2012), Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats., in J Endocrinol., 214(3), 373-380.
Regulation of placental growth by aldosterone and cortisol.
Gennari-Moser Carine, Khankin Eliyahu V, Schüller Simone, Escher Geneviève, Frey Brigitte M, Portmann C-Bettina, Baumann Marc U, Lehmann Andrea D, Surbek Daniel, Karumanchi S Ananth, Frey Felix J, Mohaupt Markus G (2011), Regulation of placental growth by aldosterone and cortisol., in Endocrinology, 152(1), 263-71.
High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome.
Escher Geneviève, Cristiano Martino, Causevic Maja, Baumann Marc, Frey Felix J, Surbek Daniel, Mohaupt Markus G (2009), High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome., in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant, 24(6), 1870-5.
Hyperaldosteronism in pregnancy.
Escher Geneviève (2009), Hyperaldosteronism in pregnancy., in Therapeutic advances in cardiovascular disease, 3(2), 123-32.
Role of CYP27A1 in progesterone metabolism in vitro and in vivo.
Escher Geneviève, Vögeli Isabelle, Escher Robert, Tuckey Robert C, Erickson Sandra, Krozowski Zygmunt, Frey Felix J (2009), Role of CYP27A1 in progesterone metabolism in vitro and in vivo., in American journal of physiology. Endocrinology and metabolism, 297(4), E949-E955.
Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo.
Mukhamedova Nigora, Escher Genevieve, D'Souza Wilissa, Tchoua Urbain, Grant Angela, Krozowski Zigmund, Bukrinsky Michael, Sviridov Dmitri (2008), Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo., in Journal of lipid research, 49(11), 2312-22.

Collaboration

Group / person Country
Types of collaboration
Institut Universitaire de Médecine Sociale et Préventive Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Universitätsklinikum Aachen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Les Cordeliers France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of California United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Baker Heart Research Institute Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
Pädiatrische Endokrinologie/Diabetologie Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Nottingham Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ISSHP XX Word Congress 2016 Talk given at a conference 1. Reduced Maternal HDL Cholesterol Efflux Capacity in women 6-8 weeks postpartum who had pre-eclampsia. 23.10.2016 Sao Paulo, Brazil Escher Geneviève;
ASMS2015 Poster Rapid screening of different groups of steroids by multiple selected ion monitoring in biological fluids. 31.05.2016 St Louis, United States of America Escher Geneviève;
IAS 2015 Poster CYP27A1 gene dosage accounts for the anti-atherosclerotic effect of Rifampicin in mice. 23.05.2016 Amsterdam, Netherlands Escher Geneviève;
ERA-EDTA Meeting 2016 Poster Reduced postpartum urinary steroid hormone synthesis in women who have experienced gestational hypertension or pre-eclampsia during pregnancy 21.05.2016 Vienna, Austria Escher Geneviève;
EAS 2015 Poster http://www.eas2015.kenes.com/ 22.03.2015 Glasgow, Great Britain and Northern Ireland Escher Geneviève;
AGLA 2015 Talk given at a conference Effect of bile acid supplementation on atherosclerosis, lipids and liver caveolin-1 expression in Cyp27A1/apoE-double knockout mice. 14.01.2015 Fribourg, Switzerland Escher Geneviève;
EASL 2013 Poster 9. Effect of hepatic CYP7A1 and CYP3A11 modulation on atherosclerosis in cyp27A1/apoE double knock out mice. 24.04.2014 Amsterdam, Netherlands Escher Geneviève;
Franco-Suisse meeting 2015 Talk given at a conference Some Good Reasons to Measure Blood Pressure in CYP27A1 KO Mice. 13.03.2014 Paris, France Escher Geneviève;
AGLA 2013 Talk given at a conference 10. Reversal of liver CYP7A1 and CYP3A11 up-regulation by cholic acid induces atherosclerosis in CYP27A1/ApoE double knockout mice. 10.01.2013 Bern, Switzerland Escher Geneviève;


Self-organised

Title Date Place
Franco-Suissse Meeting 2016 23.03.2016 Bern, Switzerland
Steroid Meeting 04.02.2016 Bern, Switzerland

Associated projects

Number Title Start Funding scheme
182482 Role of vitamin D and vitamin D metabolizing enzymes in the prevention of atherosclerosis 01.04.2019 Project funding
109774 Role of CYP27A1 in reverse cholesterol transport and atherosclerosis in vivo 01.12.2005 Project funding

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