Department of Vascular Surgery, Tianjin Union Medical Centre, 190, Jieyuan Road, Hongqiao District, Tianjin 300121, China.
Department of Vascular Surgery, Tianjin Union Medical Centre, 190, Jieyuan Road, Hongqiao District, Tianjin 300121, China.
Biochem Biophys Res Commun. 2018 Jun 22;501(2):343-350. doi: 10.1016/j.bbrc.2018.03.137. Epub 2018 May 11.
Sterol O-acyltransferase 1 (SOAT1) is a key enzyme for cholesteryl ester biosynthesis. The objective of the present study is to investigate the role and underlying molecular mechanisms of SOAT1 in atherosclerosis. Our results indicated that SOAT1 was highly expressed in endothelial cells of atherosclerotic lesions in human patients with atherosclerosis and in apolipoprotein E deficient (ApoE) mice fed with high fat diet (HFD). We established a model of atherosclerosis using ApoE and SOAT1 gene double knockout (ApoESOAT1) mice. SOAT1 alleviated HFD-induced and spontaneously developed atherosclerotic lesions in ApoE mice, accompanied with the reduced triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), while the enhanced high-density lipoprotein-cholesterol (HDL-C) in serum of ApoE mice. SOAT1 decreased collagen accumulation in the lesions. SOAT1 reduced macrophage infiltration and suppressed inflammation in ApoE mice fed with HFD, as evidenced by the decreased expressions of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor α (TNF-α). Of importance, SOAT1-attenuated inflammation was along with the inactivation of β-catenin and nuclear factor kappa B (NF-κB) ApoE mice. Moreover, oxidative stress observed in ApoE mice was inactivated by SOAT1 double knockout. In addition, expression levels of fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), protein convertase subtilisin/kexin type 9 (PCSK 9) and sterol regulatory element-binding protein-1c (SREBP-1c) were decreased in liver, peritoneal macrophages and abdominal aortas of SOAT1-knockout ApoE mice. In contrast, SOAT1 displayed improved expressions of peroxisome proliferator-activated receptor-γ (PPAR-γ) and lipoxygenase (LOX)-α in liver, peritoneal macrophages and abdominal aortas of ApoE mice. Of note, the in vitro study, oxidized low-density lipoprotein (ox-LDL) incubation reduced heme oxygenase (HO-1) expressions in human umbilical vein endothelial cells (HUVECs), which was improved by SOAT1 knockdown. Pre-treatment of sn-protoporphyrin (SnPP), an important HO-1 inhibitor, abolished the role of SOAT1 inhibition in suppressing inflammation and abnormal cholesterol transportation. These results indicated that SOAT1 deficiency protected against atherosclerosis progression via inhibiting cholesterol transportation in ApoE mice, which was, at least partly, dependent on HO-1 expressions.
甾醇 O-酰基转移酶 1（SOAT1）是胆固醇酯生物合成的关键酶。本研究旨在探讨 SOAT1 在动脉粥样硬化中的作用及其潜在的分子机制。我们的研究结果表明，SOAT1 在动脉粥样硬化患者的动脉粥样硬化病变内皮细胞和载脂蛋白 E 缺陷（ApoE）小鼠的高脂肪饮食（HFD）中高表达。我们使用 ApoE 和 SOAT1 基因双敲除（ApoESOAT1）小鼠建立了动脉粥样硬化模型。SOAT1 减轻了 ApoE 小鼠的 HFD 诱导和自发性动脉粥样硬化病变，同时降低了血清中的甘油三酯（TG）、总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C），而高密度脂蛋白胆固醇（HDL-C）升高。SOAT1 减少了病变中的胶原积累。SOAT1 减少了巨噬细胞浸润，并抑制了 HFD 喂养的 ApoE 小鼠的炎症，这表现为促炎细胞因子（包括白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子α（TNF-α））的表达降低。重要的是，SOAT1 减弱的炎症伴随着β-连环蛋白和核因子 kappa B（NF-κB）的失活。此外，在 ApoE 小鼠中观察到的氧化应激被 SOAT1 双敲除所抑制。此外，肝、腹腔巨噬细胞和腹主动脉中脂肪酸合酶（FAS）、硬脂酰辅酶 A 去饱和酶 1（SCD1）、蛋白水解酶枯草杆菌蛋白酶/激肽释放酶 9（PCSK9）和固醇调节元件结合蛋白-1c（SREBP-1c）的表达水平在 SOAT1 敲除的 ApoE 小鼠中降低。相反，SOAT1 增加了 ApoE 小鼠肝、腹腔巨噬细胞和腹主动脉中过氧化物酶体增殖物激活受体-γ（PPAR-γ）和脂氧合酶（LOX）-α的表达。值得注意的是，在体外研究中，氧化型低密度脂蛋白（ox-LDL）孵育降低了人脐静脉内皮细胞（HUVECs）中血红素加氧酶（HO-1）的表达，而 SOAT1 敲低则改善了这一表达。预先用血红素加氧酶抑制剂 sn-原卟啉（SnPP）预处理，消除了 SOAT1 抑制在抑制炎症和异常胆固醇转运中的作用。这些结果表明，SOAT1 缺乏通过抑制 ApoE 小鼠的胆固醇转运来保护动脉粥样硬化的进展，这至少部分依赖于 HO-1 的表达。
