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The role of brown adipose tissue in cholesterol metabolism: implications for the treatment of atherosclerosis

Projectomschrijving

Ontrafelen van het effect van bruin vet op de vaatwand

Bruin vet is een nieuw aangrijpingspunt in de strijd tegen cardiometabole ziekten. Dit project richt zich op het ontrafelen van het mechanisme hoe activatie van bruin vet aderverkalking voorkomt.


Dissecting the effects of brown adipose tissue on the vessel wall

Brown adipose tissue is an emerging target to combat cardiometabolic disease. This project aims to dissect the mechnism(s) how brown adipose tissue activation attenuates atherosclerosis. 

Producten

Titel: Gut microbiota play a key role in the induction of beneficial effects of butyrate on host energy metabolism
Auteur: Yanan Wang
Titel: Gut microbiota play a key role in the induction of beneficial effects of butyrate on host energy metabolism
Auteur: Zhuang Li
Titel: Anti-PCSK9 treatment enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice
Auteur: Enchen Zhou
Titel: Bile acid sequestrant colesevelam enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice
Auteur: Yanan Wang
Titel: Butyrate via the gut-brain neural circuit?reduces appetite and activates brown adipose tissue
Auteur: Yanan Wang
Titel: Bile acid sequestrant colesevelam enhances beneficial effects of brown fat activation on cholesterol metabolism and atherosclerosis development in APOE*3-Leiden.CETP mice
Auteur: Enchen Zhou
Titel: Anti-PCSK9 treatment enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice
Auteur: Enchen Zhou
Titel: Lipopolysaccharide reduces hepatic cholesteryl ester transfer protein expression by activating Kupffer cells
Auteur: Yanan Wang
Titel: Butyrate via the gut-brain neuronal circuit reduces appetite and activates brown adipose tissue
Auteur: Li, Zhuang, Kooijman, Sander, Yi, Chunxia, Chuang, Chih Kit, Berbée, Jimmy F.P., Willems Van Dijk, Ko, Groen, Albert K., Rensen, Patrick C.N., Wang, Yanan
Magazine: Atherosclerosis
Titel: Butyrate via the gut-brain neural circuit reduces appetite and activates brown adipose tissue
Auteur: Wang, Y., Li, Z., Yi, C.X., Katiraei, S., Kooijman, S., Zhou, E., Chung, C., Gao, Y., van den Heuvel, J.K., Meijer, O.C., Berbée, J.F.P., Heijink, M., Giera, M., Willems van Dijk, J.A.P., Groen, A.K., Rensen, P.C.N.
Magazine: Atherosclerosis
Titel: Anti-Pcsk9 Treatment Enhances Beneficial Effects Of Brown Fat Activation On Cholesterol Metabolism In Apoe*3-Leiden.Cetp Mice
Auteur: Zhou, E., Li, Z., Choukoud, A., Berbée, J.F.P., Kooijman, S., Rensen, P.C.N., Wang, Y.
Magazine: Atherosclerosis
Titel: Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development
Auteur: Zhou, Enchen, Hoeke, Geerte, Li, Zhuang, Eibergen, Arthur C, Schonk, Amber W, Koehorst, Martijn, Boverhof, Renze, Havinga, Rick, Kuipers, Folkert, Coskun, Tamer, Boon, Mariëtte R, Groen, Albert K, Rensen, Patrick C N, Berbée, Jimmy F P, Wang, Yanan
Magazine: Cardiovascular Research
Titel: Statin treatment potentiates the lipid-lowering and anti-atherogenic effect of bat activation by accelerating lipoprotein remnant clearance
Auteur: Hoeke, Geerte, Wang, Yanan, Van Dam, Andrea, Mol, Isabel, Van Den Berg, Susan, Groen, Albert, Rensen, Patrick, Berbée, Jimmy, Boon, Mariëtte
Magazine: Atherosclerosis
Titel: Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis
Auteur: Hoeke, Geerte, Wang, Yanan, van Dam, Andrea D., Mol, Isabel M., Gart, Eveline, Klop, Henk G., van den Berg, Susan M., Pieterman, Elsbet H., Princen, Hans M.G., Groen, Albert K., Rensen, Patrick C.N., Berbée, Jimmy F.P., Boon, Mariëtte R.
Magazine: Atherosclerosis
Titel: The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1
Auteur: Herrera Moro Chao, Daniela, Wang, Yanan, Foppen, Ewout, Ottenhoff, Roelof, van Roomen, Cindy, Parlevliet, Edwin T., van Eijk, Marco, Verhoek, Marri, Boot, Rolf, Marques, Andre R., Scheij, Saskia, Mirzaian, Mina, Kooijman, Sander, Jansen, Kirstin, Wang, Dawei, Mergen, Clarita, Seeley, Randy J., Tschöp, Matthias H., Overkleeft, Herman, Rensen, Patrick C.N., Kalsbeek, Andries, Aerts, Johannes M.F.G., Yi, Chun-Xia
Magazine: Diabetes
Titel: FXR activation normalizes dyslipidemia and alleviates obesity in western-type diet–fed APOE*3-Leiden.CETP transgenic mice
Auteur: Paalvast, Y., Zhou, E., Mulder, N.L., Koehorst, M., Boverhof, R., Willems van Dijk, K., Rensen, P.C.N., Kuivenhoven, J.A., Kremoser, C., Wang, Y., Kuipers, F., Groen, A.K., de Boer, J.F.
Magazine: Atherosclerosis
Titel: Inhibition of ?24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution
Auteur: Körner, Andreas, Zhou, Enchen, Müller, Christoph, Mohammed, Yassene, Herceg, Sandra, Bracher, Franz, Rensen, Patrick C. N., Wang, Yanan, Mirakaj, Valbona, Giera, Martin
Magazine: PNAS
Titel: Bile acid sequestrant colesevelam enhances beneficial effects of brown fat activation on cholesterol metabolism in APOE*3-Leiden.CETP mice
Auteur: Zhou, E., Hoeke, G., Eibergen, A.C., Wang, Z., Havinga, R.H., Groen, A.K., Boon, M.R., Rensen, P.C.N., Berbee, J.F.P., Wang, Y.
Magazine: Atherosclerosis
Titel: In vivo and in silico dynamics of the development of Metabolic Syndrome
Auteur: Rozendaal, Yvonne J. W., Wang, Yanan, Paalvast, Yared, Tambyrajah, Lauren L., Li, Zhuang, Willems van Dijk, Ko, Rensen, Patrick C. N., Kuivenhoven, Jan A., Groen, Albert K., Hilbers, Peter A. J., van Riel, Natal A. W.
Magazine: PLoS Computational Biology
Titel: Computational modelling of energy balance in individuals with Metabolic Syndrome
Auteur: Rozendaal, Yvonne J. W., Wang, Yanan, Hilbers, Peter A. J., van Riel, Natal A. W.
Magazine: BMC Systems Biology
Titel: Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit
Auteur: Li, Zhuang, Yi, Chun-Xia, Katiraei, Saeed, Kooijman, Sander, Zhou, Enchen, Chung, Chih Kit, Gao, Yuanqing, van den Heuvel, José K, Meijer, Onno C, Berbée, Jimmy F P, Heijink, Marieke, Giera, Martin, Willems van Dijk, Ko, Groen, Albert K, Rensen, Patrick C N, Wang, Yanan
Magazine: Gut
Link: http://dx.doi.org/10.1136/gutjnl-2017-314050
Titel: CETP (Cholesteryl Ester Transfer Protein) Concentration A Genome-Wide Association Study Followed by Mendelian Randomization on Coronary Artery Disease
Auteur: Blauw, Lisanne L., Li-Gao, Ruifang, Noordam, Raymond, de Mutsert, Renée, Trompet, Stella, Berbée, Jimmy F.P., Wang, Yanan, van Klinken, Jan B., Christen, Tim, van Heemst, Diana, Mook-Kanamori, Dennis O., Rosendaal, Frits R., Jukema, J. Wouter, Rensen, Patrick C.N., Willems van Dijk, Ko
Magazine: Circulation: Cardiovascular Genetics
Titel: Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile
Auteur: Blauw, Lisanne L., Noordam, Raymond, Soidinsalo, Sebastian, Blauw, C. Alexander, Li-Gao, Ruifang, de Mutsert, Renée, Berbée, Jimmy F. P., Wang, Yanan, van Heemst, Diana, Rosendaal, Frits R., Jukema, J. Wouter, Mook-Kanamori, Dennis O., Würtz, Peter, Willems van Dijk, Ko, Rensen, Patrick C. N.
Magazine: European Journal of Human Genetics
Titel: Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis
Auteur: Hoeke, Geerte, Wang, Yanan, van Dam, Andrea D., Mol, Isabel M., Gart, Eveline, Klop, Henk G., van den Berg, Susan M., Pieterman, Elsbet H., Princen, Hans M.G., Groen, Albert K., Rensen, Patrick C.N., Berbée, Jimmy F.P., Boon, Mariëtte R.
Magazine: Atherosclerosis
Titel: Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis
Auteur: Hoeke, Geerte, Wang, Yanan, van Dam, Andrea D., Mol, Isabel M., Gart, Eveline, Klop, Henk G., van den Berg, Susan M., Pieterman, Elsbet H., Princen, Hans M.G., Groen, Albert K., Rensen, Patrick C.N., Berbée, Jimmy F.P., Boon, Mariëtte R.
Magazine: Atherosclerosis
Titel: Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80(+)Clec4f(+)Vsig4(+)Ly6C(-) Kupffer Cell Subsets
Auteur: van der Tuin, Sam J. L., Li, Zhuang, Berbée, Jimmy F. P., Verkouter, Inge, Ringnalda, Linda E., Neele, Annette E., van Klinken, Jan B., Rensen, Sander S., Fu, Jingyuan, de Winther, Menno P. J., Groen, Albert K., Rensen, Patrick C. N., Willems van Dijk, Ko, Wang, Yanan
Magazine: Journal of the American Heart Association

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Samenvatting van de aanvraag

Background: Only since 2009, brown adipose tissue (BAT) was shown to be present in adult humans and to contribute substantially to triglyceride metabolism. Very recently, we showed that BAT activation also attenuates atherosclerosis, but underlying mechanisms are still rather obscure. Intriguingly, pilot data show that BAT activation enhances (V)LDL remnant clearance, and generates lipoprotein surface remnants that may drive reverse cholesterol transport (RCT) to facilitate cholesterol removal. Hypothesis: BAT activation attenuates atherosclerosis by enhancing both the clearance of (V)LDL remnants and the production of lipoprotein surface remnants, which drives RCT to facilitate cholesterol removal. Objectives: 1) To determine the role of lowering plasma (V)LDL versus generation of surface remnants in the anti-atherogenic effect of BAT activation. 2) To dissect the contribution of the (V)LDL versus HDL pathways to cholesterol removal upon BAT activation by using computational modelling. 3) To evaluate the additive/synergistic effect of BAT activation combined with lipid-lowering strategies on the treatment of dyslipidemia and atherosclerosis. Approach: 1) BAT will be (in)activated in mice, and the role of (V)LDL remnant clearance versus RCT in atherosclerosis development will be delineated using siRNA-mediated silencing of pathway-specific proteins. 2) Plasma samples from a dedicated human study on BAT activation will be screened for dynamic changes in lipid metabolites by 1H-NMR. Computational modelling of (V)LDL and HDL kinetics will be exploited to dissect the involvement of (V)LDL and HDL pathways in BAT activation-induced cholesterol removal. 3) We will assess the possible additive/synergistic effects of BAT activation on top of current lipid lowering strategies (statin, PCSK9 inhibitor and ezetimibe) on the progression and regression of atherosclerosis. Expected results: These studies will elucidate the role of lowering (V)LDL and generation of surface remnants in the beneficial effects of BAT activation on atherosclerosis development, and identify novel therapeutic strategies to combat cardiovascular disease.

Onderwerpen

Kenmerken

Projectnummer:
91617027
Looptijd: 100%
Looptijd: 100 %
2016
2020
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. Y. Wang
Verantwoordelijke organisatie:
Leiden University Medical Center