Ge Xiaoke, Slütter Bram, Lambooij Joost M, Zhou Enchen, Ying Zhixiong, Agirman Ceren, Heijink Marieke, Rimbert Antoine, Guigas Bruno, Kuiper Johan, Müller Christoph, Bracher Franz, Giera Martin, Kooijman Sander, Rensen Patrick C N, Wang Yanan, Schönke Milena
Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
Div. of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333 AL, the Netherlands.
iScience. 2024 Apr 26;27(6):109830. doi: 10.1016/j.isci.2024.109830. eCollection 2024 Jun 21.
The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model.
肝脏X受体（LXR）被认为是动脉粥样硬化治疗的一个靶点，但合成的LXR激动剂通常也会导致肝脂肪变性和高甘油三酯血症。羊毛甾醇是胆固醇生物合成的最终中间体，已被确定为一种选择性LXR配体，可抑制炎症而不诱导脂肪生成。Δ24-脱氢胆固醇还原酶（DHCR24）将羊毛甾醇转化为胆固醇，我们之前表明，DHCR24抑制剂SH42可增加羊毛甾醇以激活LXR，并减轻实验性腹膜炎和代谢功能障碍相关脂肪性肝病。在此，我们旨在评估SH42对载脂蛋白E∗3-莱顿.CETP小鼠和低密度脂蛋白（LDL）受体敲除小鼠动脉粥样硬化发展的影响，这两种小鼠模型分别用于模拟脂质和炎症驱动的动脉粥样硬化。在这两种模型中，SH42增加了羊毛甾醇，但不影响血浆脂质。SH42在降低载脂蛋白E∗3-莱顿.CETP小鼠肝脏脂质的同时，调节了LDL受体敲除小鼠循环单核细胞的数量，但在这两种模型中均未减轻动脉粥样硬化。
