TY - JOUR
T1 - The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice
AU - in Het Panhuis, Wietse
AU - Thiemann, Ellen
AU - van Dijk, Daisy M. A. H.
AU - Been, Bibian
AU - Jarrett, Kelsey E.
AU - Meurs, Amber
AU - Kooijman, Sander
AU - Hovingh, Milaine V.
AU - Modder, Melanie
AU - van Os, Bram W.
AU - Sluiter, Thijs J.
AU - Blomberg, Niek
AU - Pronk, Amanda C. M.
AU - Afkir, Salwa
AU - Streefland, Trea C. M.
AU - Lalai, Reshma A.
AU - Taveras, Maria O.
AU - Zhang, Sen
AU - Adams, Timothy E.
AU - Terry, Lauren V.
AU - Turpin-Nolan, Sarah M.
AU - de Vries, Margreet R.
AU - Giera, Martin
AU - Rose-John, Stefan
AU - Zelcer, Noam
AU - de Boer, Jan Freark
AU - de Aguiar Vallim, Thomas Q.
AU - Febbraio, Mark A.
AU - Rensen, Patrick C. N.
AU - Schönke, Milena
N1 - Publisher Copyright:
© 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2025/10/24
Y1 - 2025/10/24
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105019999575
U2 - 10.1126/sciadv.adx3794
DO - 10.1126/sciadv.adx3794
M3 - Article
C2 - 41134879
SN - 2375-2548
VL - 11
SP - eadx3794
JO - Science advances
JF - Science advances
IS - 43
M1 - eadx3794
ER -
SDG 3 Good Health and Well-being