Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8292532 | Biochemical and Biophysical Research Communications | 2018 | 8 Pages |
Abstract
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 (ApoEâ/-) mice fed with high fat diet (HFD). We established a model of atherosclerosis using ApoE and SOAT1 gene double knockout (ApoEâ/âSOAT1â/â) mice. SOAT1â/â alleviated HFD-induced and spontaneously developed atherosclerotic lesions in ApoEâ/- 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 ApoEâ/- mice. SOAT1â/â decreased collagen accumulation in the lesions. SOAT1â/â reduced macrophage infiltration and suppressed inflammation in ApoEâ/â 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, SOAT1â/â-attenuated inflammation was along with the inactivation of β-catenin and nuclear factor kappa B (NF-κB) ApoEâ/- mice. Moreover, oxidative stress observed in ApoEâ/- 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 ApoEâ/- mice. In contrast, SOAT1â/â displayed improved expressions of peroxisome proliferator-activated receptor-γ (PPAR-γ) and lipoxygenase (LOX)-α in liver, peritoneal macrophages and abdominal aortas of ApoEâ/- 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 ApoEâ/- mice, which was, at least partly, dependent on HO-1 expressions.
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Authors
Nan Wu, Rong-Qing Li, Li Li,