SOAT1 deficiency attenuates atherosclerosis by regulating inflammation and cholesterol transportation via HO-1 pathway.

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.