Science advances · 2025
The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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In Het Panhuis Wietse, Thiemann Ellen, van Dijk Daisy M A H, Been Bibian, Jarrett Kelsey E, Meurs Amber, Kooijman Sander, Hovingh Milaine V, Modder Melanie, van Os Bram W, Sluiter Thijs J, Blomberg Niek, Pronk Amanda C M, Afkir Salwa, Streefland Trea C M, Lalai Reshma A, Taveras Maria O, Zhang Sen, Adams Timothy E, Terry Lauren V, Turpin-Nolan Sarah M, de Vries Margreet R, Giera Martin, Rose-John Stefan, Zelcer Noam, de Boer Jan Freark, de Aguiar Vallim Thomas Q, Febbraio Mark A, Rensen Patrick C N, Schönke Milena
Аннотация
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.