2026-06-08T01:05:51Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/949302025-03-18T13:21:59Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Senatus, Laura author Egaña-Gorroño, Lander author López-Díez, Raquel author Bergaya, Sonia author Aranda Gómez, Juan Francisco author Amengual, Jaume author Lakshmi, Arivazhagan author Manigrasso, Michaele author Yepuri, Gautham author Nimma, Ramesh author Mangar, Kaamashri author Bernadin, Rollanda author Zhou, Boyan author Gugger, Paul author Li, Huilin author Friedman, Richard author Theise, Neil author Shekhtman, Alexander author Fisher, Edward author Ramasamy Ravichandran author Schmidt Ann Marie author 2023 Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr−/− mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr−/− mice, male Ldlr−/− Diaph1−/− mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr−/− Diaph1−/− mice displayed significantly less atherosclerosis compared to Ldlr−/− mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1. Senatus, L., Egaña-Gorroño, L., López-Díez, R. et al. DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice. Commun Biol 6, 280 (2023). https://doi.org/10.1038/s42003-023-04643-2 2399-3642 10.1038/s42003-023-04643-2 https://hdl.handle.net/20.500.14352/94930 https://doi.org/10.1038/s42003-023-04643-2 DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice