The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice
The chimeric cytokine IC7Fc conveys the metabolic signaling properties of the glycoprotein 130 receptor cytokines interleukin-6 and ciliary neurotrophic factor via membrane-bound signaling. IC7Fc was previously shown to slow the progression of type 2 diabetes mellitus, and here, we demonstrate its effect on atherosclerotic development. In APOE*3-Leiden.CETP mice, an atherosclerosis-prone model with a humanized lipoprotein metabolism, IC7Fc markedly lowered plasma triglyceride and total cholesterol levels. This was mechanistically explained by an inhibition of de novo lipogenesis in the liver, increased synthesis of bile acids from cholesterol, and down-regulated apolipoprotein B synthesis, which resulted in decreased cholesterol secretion in very low-density lipoprotein particles. As a consequence, IC7Fc treatment considerably reduced atherosclerotic lesion formation and vascular inflammation compared with current antihyperlipidemic therapy. In conclusion, IC7Fc is a promising pharmacological treatment for cardiometabolic diseases targeting hyperlipidemia and inflammation.
Authors
- Amber Meurs (ORCID: https://orcid.org/0000-0003-1271-9154)
- Mark A. Febbraio (ORCID: https://orcid.org/0000-0002-9296-4418)
- E Thiemann
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Kelsey E. Jarrett (ORCID: https://orcid.org/0000-0001-5358-8280)
- Salwa Afkir
- Sander Kooijman (ORCID: https://orcid.org/0000-0002-0014-5571)
- Patrick C.N. Rensen (ORCID: https://orcid.org/0000-0002-8455-4988)
- Amanda C. M. Pronk
- Bram W. van Os (ORCID: https://orcid.org/0000-0002-2327-0527)
- Trea C.M. Streefland
- Milaine V. Hovingh
- Thomas Q. de Aguiar Vallim (ORCID: https://orcid.org/0000-0001-7642-5046)
- Thijs J. Sluiter (ORCID: https://orcid.org/0000-0003-0199-2729)
- Noam Zelcer (ORCID: https://orcid.org/0000-0001-6935-7532)
- Milena Schönke (ORCID: https://orcid.org/0000-0003-2030-6958)
- Lauren V. Terry (ORCID: https://orcid.org/0000-0003-4538-5744)
- Melanie Modder (ORCID: https://orcid.org/0000-0002-8715-1586)
- Timothy E. Adams (ORCID: https://orcid.org/0000-0003-3436-0066)
- Margreet R. de Vries (ORCID: https://orcid.org/0000-0002-3648-9130)
- Reshma A. Lalai
- Sarah M. Turpin-Nolan (ORCID: https://orcid.org/0000-0002-7469-7934)
- Stefan Rose‐John (ORCID: https://orcid.org/0000-0002-7519-3279)
- Wietse In het Panhuis (ORCID: https://orcid.org/0000-0002-4394-6387)
- Jan Freark de Boer (ORCID: https://orcid.org/0000-0001-6759-3291)
- Sen Zhang (ORCID: https://orcid.org/0000-0001-7899-0268)
- Maria Taveras
- Niek Blomberg
- Daisy Maria Alberta Hendrika van Dijk (ORCID: https://orcid.org/0009-0001-2531-2292)
- Bibian Been
Institutions
- Brigham and Women's Hospital (US)
- University Medical Center Groningen (NL)
- Harvard University (US)
- University of California, Los Angeles (US)
- University of Groningen (NL)
- Leiden University Medical Center (NL)
- Christian-Albrechts-Universität zu Kiel (DE)
- Netherlands Metabolomics Centre (NL)
- Amsterdam Neuroscience (NL)
- Amsterdam University Medical Centers (NL)
- Institute for Atherosclerosis Research (RU)
- CSIRO Manufacturing (AU)
- Institute of Infection and Immunity (CA)
- Monash University (AU)
- University of Amsterdam (NL)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1126/sciadv.adx3794
- Citations
- 1
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Universiteit Leiden
- Novo Nordisk