Nuclear receptor Dax1 promotes atherosclerosis by lipid transport inhibition and autophagy suppression in macrophages

作者：Feifei Li, Yixuan Wang, Shuai Chen, Jingmeng Liu, Xinrui Wu, Yipaerguli Maimati, Fenghua Ding, Xiao Qun Wang, Ying Shen, Qiujing Chen, Yunqi Li, Weifeng Shen, Ruiyan Zhang, Yang Dai, Lin Lu · 发表于：European Heart Journal · 年份：2025 · DOI：10.1093/eurheartj/ehaf241 · 被引用次数：12 · 研究领域：Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities、Cholesterol and Lipid Metabolism、Nuclear Receptors and Signaling

BACKGROUND AND AIMS: Nuclear receptors (NRs) are involved in cardiovascular physiology and pathology. Dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (Dax1) is a co-repressor of several protective NRs. However, whether Dax1 influences atherosclerosis remains unclear. This study aims to explore the role of Dax1 in atherogenesis and find a pharmacological approach targeting Dax1 to prevent atherosclerosis. METHODS: Dax1 levels were examined in human atherosclerotic arteries. Atherosclerosis animal models were established in mice with macrophage-specific Dax1 knockdown following AAV8-PCSK9 administration and double knockout of macrophage Dax1 and ApoE to evaluate the role of Dax1. Transcriptomic and proteomic analyses were employed to decipher the underlying mechanisms. 2'-Deoxycytidine, an inhibitor of Dax1, was used to verify the effects of Dax1 in macrophages and in mice with atherosclerosis. RESULTS: Dax1 mRNA level was up-regulated among NRs in atherosclerotic arteries compared to non-atherosclerotic arteries. The elevation of Dax1 was prominent in the macrophages of atherosclerotic arteries. Macrophage-specific Dax1 knockout mice had less atherosclerosis than controls. Mechanistically, Dax1 inhibited liver X receptor alpha (LXRα), and interacted directly with transcription factor EB (TFEB) to suppress autophagy, resulting in lipid accumulation and inflammation in macrophages. Additionally, 2'-deoxycytidine concentrati...