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

Abstract 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 concentration dependently decreased Dax1 levels, enhanced autophagy, reduced lipid accumulation, and inhibited atherosclerosis in mice. Conclusions This study demonstrates that Dax1 levels are increased in atherosclerotic plaques. Dax1 promotes atherosclerosis by interacting with TFEB to suppress autophagy and inhibiting LXRα for lipid transport in macrophage, indicating that Dax1 is a potential target for atherosclerosis.