Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.
Commun Biol. 2023 Mar 17;6(1):280. doi: 10.1038/s42003-023-04643-2.
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.
动脉粥样硬化通过失调的脂质代谢与过度炎症交织发展。先前有研究提示晚期糖基化终产物受体(RAGE)在动脉粥样硬化中发挥作用,这促使我们探索 RAGE 胞质结构域结合蛋白 Diahanas1(DIAPH1)是否也参与了这些过程。我们将动脉粥样硬化易感型 Ldlr 小鼠与缺乏 Diaphan1 的小鼠进行杂交,并喂养它们西方饮食 16 周。与雄性 Ldlr 小鼠相比,雄性 Ldlr Diaph1 小鼠的动脉粥样硬化明显减少,同时血浆胆固醇和甘油三酯浓度降低。与 Ldlr 小鼠相比,雌性 Ldlr Diaph1 小鼠的动脉粥样硬化明显减少,且血浆胆固醇浓度降低,但血浆甘油三酯浓度无差异。在雄性小鼠中,删除 Diaphan1 可减弱调节肝脂质代谢的基因 Acaca、Acacb、Gpat2、Lpin1、Lpin2 和 Fasn 的表达,但对上游转录因子 Srebf1、Srebf2 或 Mxlipl 的 mRNA 表达无影响。我们发现,SREBP1 的核易位依赖于 DIAPH1,但不依赖于碳水化合物或胰岛素调节信号,至少部分依赖于肌动蛋白细胞骨架。这项工作揭示了 DIAPH1 通过新的机制调控动脉粥样硬化和脂质代谢。