DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice

Laura Senatus, Lander Egaña-Gorroño, Raquel López-Díez, Sonia Bergaya, Juan Francisco Aranda, Jaume Amengual, Lakshmi Arivazhagan, Michaele B. Manigrasso, Gautham Yepuri, Ramesh Nimma, Kaamashri N. Mangar, Rollanda Bernadin, Boyan Zhou, Paul F. Gugger, Huilin Li, Richard A. Friedman, Neil D. Theise, Alexander Shekhtman, Edward A. Fisher, Ravichandran RamasamyAnn Marie Schmidt

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Article number280
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023
Externally publishedYes

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