Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidaemia and atherosclerosis development in APOE*3-Leiden.CETP mice

被引：5

作者：

Modder, Melanie ^{[1
,2
]}

Panhuis, Wietse In Het ^{[1
,2
]}

Li, Mohan ^{[1
,2
]}

Afkir, Salwa ^{[1
,2
]}

Dorn, Alexandra L. ^{[1
,2
]}

Pronk, Amanda C. M. ^{[1
,2
]}

Streefland, Trea C. M. ^{[1
,2
]}

Lalai, Reshma A. ^{[1
,2
]}

Pierrou, Stefan ^{[3
]}

Nilsson, Stefan K. ^{[3
]}

Olivecrona, Gunilla ^{[3
,4
]}

Kooijman, Sander ^{[1
,2
]}

Rensen, Patrick C. N. ^{[1
,2
]}

Schonke, Milena ^{[1
,2
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Med, Div Endocrinol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[3] Lipigon Pharmaceut AB, Tvistevagen 48C, S-90736 Umea, Sweden

[4] Umea Univ, Dept Med Biosci, Umea, Sweden

来源：

CARDIOVASCULAR RESEARCH | 2024年 / 120卷 / 17期

关键词：

Hyperlipidaemia; Atherosclerosis; Angptl3; Angptl4; Antisense oligonucleotides; DENSITY-LIPOPROTEIN; TRANSGENIC MICE; VARIANTS; RISK; ASSOCIATION; INHIBITION; EVINACUMAB; CLEARANCE; LIPASE;

D O I：

10.1093/cvr/cvae195

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism.Methods and results Mice were subcutaneously injected twice per week with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance, and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma TGs (-48%) and total cholesterol (-56%), explained by higher VLDL-derived FA uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma TGs in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma TGs independent of the nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects.Conclusion Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing. Graphical Abstract

引用

页码：2179 / 2190

页数：12

共 51 条

[1] Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis [J].

Aryal, Binod ;

Singh, Abhishek K. ;

Zhang, Xinbo ;

Varela, Luis ;

Rotllan, Noemi ;

Goedeke, Leigh ;

Chaube, Balkrishna ;

Camporez, Joao-Paulo ;

Vatner, Daniel F. ;

Horvath, Tamas L. ;

Shulman, Gerald I. ;

Suarez, Yajaira ;

Fernandez-Hernando, Carlos .

JCI INSIGHT, 2018, 3 (06)

[2] Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development [J].

Berbee, Jimmy F. P. ;

Boon, Mariette R. ;

Khedoe, P. Padmini S. J. ;

Bartelt, Alexander ;

Schlein, Christian ;

Worthmann, Anna ;

Kooijman, Sander ;

Hoeke, Geerte ;

Mol, Isabel M. ;

John, Clara ;

Jung, Caroline ;

Vazirpanah, Nadia ;

Brouwers, Linda P. J. ;

Gordts, Philip L. S. M. ;

Esko, Jeffrey D. ;

Hiemstra, Pieter S. ;

Havekes, Louis M. ;

Scheja, Ludger ;

Heeren, Joerg ;

Rensen, Patrick C. N. .

NATURE COMMUNICATIONS, 2015, 6

[3]

BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911

[4] Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel [J].

Boren, Jan ;

Chapman, M. John ;

Krauss, Ronald M. ;

Packard, Chris J. ;

Bentzon, Jacob F. ;

Binder, Christoph J. ;

Daemen, Mat J. ;

Demer, Linda L. ;

Hegele, Robert A. ;

Nicholls, Stephen J. ;

Nordestgaard, Brge G. ;

Watts, Gerald F. ;

Bruckert, Eric ;

Fazio, Sergio ;

Ference, Brian A. ;

Graham, Ian ;

Horton, Jay D. ;

Landmesser, Ulf ;

Laufs, Ulrich ;

Masana, Luis ;

Pasterkamp, Gerard ;

Raal, Frederick J. ;

Ray, Kausik K. ;

Schunkert, Heribert ;

Taskinen, Marja-Riitta ;

van de Sluis, Bart ;

Wiklund, Olov ;

Tokgozoglu, Lale ;

Catapano, Alberico L. ;

Ginsberg, Henry N. .

EUROPEAN HEART JOURNAL, 2020, 41 (24) :2313-+

[5] Identification of a mammalian angiopoietin-related protein expressed specifically in liver [J].

Conklin, D ;

Gilbertson, D ;

Taft, DW ;

Maurer, MF ;

Whitmore, TE ;

Smith, DL ;

Walker, KM ;

Chen, LH ;

Wattler, S ;

Nehls, M ;

Lewis, KB .

GENOMICS, 1999, 62 (03) :477-482

[6] ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy [J].

Deng, Mingjuan ;

Kutrolli, Elda ;

Sadewasser, Anne ;

Michel, Sven ;

Joibari, Masoumeh Motamedi ;

Jaschinski, Frank ;

Olivecrona, Gunilla ;

Nilsson, Stefan K. ;

Kersten, Sander .

JOURNAL OF LIPID RESEARCH, 2022, 63 (07)

[7] Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice [J].

Desai, Urvi ;

Lee, E-Chiang ;

Chung, Kyu ;

Gao, Cuihua ;

Gay, Jason ;

Key, Billie ;

Hansen, Gwenn ;

Machajewski, Dennis ;

Platt, Kenneth A. ;

Sands, Arthur T. ;

Schneider, Matthias ;

Van Sligtenhorst, Isaac ;

Suwanichkul, Adisak ;

Vogel, Peter ;

Wilganowski, Nat ;

Wingert, June ;

Zambrowicz, Brian P. ;

Landes, Greg ;

Powell, David R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (28) :11766-11771

[8] Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease [J].

Dewey, F. E. ;

Gusarova, V. ;

Dunbar, R. L. ;

O'Dushlaine, C. ;

Schurmann, C. ;

Gottesman, O. ;

McCarthy, S. ;

Van Hout, C. V. ;

Bruse, S. ;

Dansky, H. M. ;

Leader, J. B. ;

Murray, M. F. ;

Ritchie, M. D. ;

Kirchner, H. L. ;

Habegger, L. ;

Lopez, A. ;

Penn, J. ;

Zhao, A. ;

Shao, W. ;

Stahl, N. ;

Murphy, A. J. ;

Hamon, S. ;

Bouzelmat, A. ;

Zhang, R. ;

Shumel, B. ;

Pordy, R. ;

Gipe, D. ;

Herman, G. A. ;

Sheu, W. H. H. ;

Lee, I-T. ;

Liang, K. -W. ;

Guo, X. ;

Rotter, J. I. ;

Chen, Y. -D. I. ;

Kraus, W. E. ;

Shah, S. H. ;

Damrauer, S. ;

Small, A. ;

Rader, D. J. ;

Wulff, A. B. ;

Nordestgaard, B. G. ;

Tybjaerg-Hansen, A. ;

van den Hoek, A. M. ;

Princen, H. M. G. ;

Ledbetter, D. H. ;

Carey, D. J. ;

Overton, J. D. ;

Reid, J. G. ;

Sasiela, W. J. ;

Banerjee, P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 377 (03) :211-221

[9] Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease [J].

Dewey, Frederick F. ;

Gusarova, Viktoria ;

O'Dushlaine, Colm ;

Gottesman, Omri ;

Trejos, Jesus ;

Hunt, Charleen ;

Van Hout, Cristopher V. ;

Habegger, Lukas ;

Buckler, David ;

Lai, Ka-Man V. ;

Leader, Joseph B. ;

Murray, Michael F. ;

Ritchie, Marylyn D. ;

Kirchner, H. Lester ;

Ledbetter, David H. ;

Penn, John ;

Lopez, Alexander ;

Borecki, Ingrid B. ;

Overton, John D. ;

Reid, Jeffrey G. ;

Carey, David J. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Baras, Aris ;

Gromada, Jesper ;

Shuldiner, Alan R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (12) :1123-1133

[10] ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure [J].

Dijk, Wieneke ;

Heine, Markus ;

Vergnes, Laurent ;

Boon, Mariette R. ;

Schaart, Gert ;

Hesselink, Matthijs K. C. ;

Reue, Karen ;

Lichtenbelt, Wouter D. van Marken ;

Olivecrona, Gunilla ;

Rensen, Patrick C. N. ;

Heeren, Joerg ;

Kersten, Sander .

ELIFE, 2015, 4

← 1 2 3 4 5 6 →