关键词： ACER2/3, alkaline ceramidase 2/3 APOE, apolipoprotein E ARNT, aryl hydrocarbon nuclear translocator Adipocyte Atherosclerosis CCL5, chemokine (C–C motif) ligand 5 CERS2/4/5/6, ceramide synthase 2/4/5/6 CXCL1, chemokine (C–X–C motif) ligand 1 protein Ceramide ChIP, chromatin immunoprecipitation Cholesterol CoCl2, cobalt(Ⅱ) chloride DEGS1, delta(4)-desaturase, sphingolipid 1 EIF5, eukaryotic translation initiation factor 5 GFP, green fluorescent protein HDL, high-density lipoprotein HIF-1α HIF-1α/2α/3α, hypoxia-inducible factor 1 alpha/2 alpha/3 alpha HREs, HIF-response elements IL-6/1β, interleukin-6/1β Inflammatory responses LDL, low-density lipoprotein MAC-2, lectin, galactose binding, soluble 3 MCP-1, monocyte chemoattractant protein-1 PC, phosphatidylcholine PLS-DA, partial least squares discriminant analysis PX-478 SGMS1, sphingomyelin synthase 1 SM, sphingomyelin SMPD1/2/3/4, sphingomyelin phosphodiesterase 1/2/3/4 SMPD3 SMase, sphingomyelinase SPTLC1/2/3, serine palmitoyltransferase long chain base subunit 1/2/3 TNF-α, tumor necrosis factor alpha VEGF, vascular endothelial growth factor VIP, variable importance for the projection VLDL, very low-density lipoprotein eWAT, epididymal white adipose tissue ACER2/3, alkaline ceramidase 2/3 APOE, apolipoprotein E ARNT, aryl hydrocarbon nuclear translocator Adipocyte Atherosclerosis CCL5, chemokine (C–C motif) ligand 5 CERS2/4/5/6, ceramide synthase 2/4/5/6 CXCL1, chemokine (C–X–C motif) ligand 1 protein Ceramide ChIP, chromatin immunoprecipitation Cholesterol CoCl2, cobalt(Ⅱ) chloride DEGS1, delta(4)-desaturase, sphingolipid 1 EIF5, eukaryotic translation initiation factor 5 GFP, green fluorescent protein HDL, high-density lipoprotein HIF-1α HIF-1α/2α/3α, hypoxia-inducible factor 1 alpha/2 alpha/3 alpha HREs, HIF-response elements IL-6/1β, interleukin-6/1β Inflammatory responses LDL, low-density lipoprotein MAC-2, lectin, galactose binding, soluble 3 MCP-1, monocyte chemoattractant protein-1 PC, phosphatidylcholine PLS-DA, partial least squares discriminant analysis PX-478 SGMS1, sphingomyelin synthase 1 SM, sphingomyelin SMPD1/2/3/4, sphingomyelin phosphodiesterase 1/2/3/4 SMPD3 SMase, sphingomyelinase SPTLC1/2/3, serine palmitoyltransferase long chain base subunit 1/2/3 TNF-α, tumor necrosis factor alpha VEGF, vascular endothelial growth factor VIP, variable importance for the projection VLDL, very low-density lipoprotein eWAT, epididymal white adipose tissue

来  源：   DOI：10.1016/j.apsb.2021.10.001   PDF(Pubmed)

Abstract：
Atherosclerosis is a chronic multifactorial cardiovascular disease. Western diets have been reported to affect atherosclerosis through regulating adipose function. In high cholesterol diet-fed ApoE -/- mice, adipocyte HIF-1α deficiency or direct inhibition of HIF-1α by the selective pharmacological HIF-1α inhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation, which lowers cholesterol levels and reduces inflammatory responses, resulting in improved dyslipidemia and atherogenesis. Smpd3, the gene encoding neutral sphingomyelinase, is identified as a new target gene directly regulated by HIF-1α that is involved in ceramide generation. Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice. Therefore, HIF-1α inhibition may constitute a novel approach to slow atherosclerotic progression.
摘要：
动脉粥样硬化是一种慢性多因素心血管疾病。据报道，西方饮食通过调节脂肪功能影响动脉粥样硬化。在高胆固醇饮食喂养的ApoE-/-小鼠中，脂肪细胞HIF-1α缺乏或通过选择性药理学HIF-1α抑制剂PX-478直接抑制HIF-1α，通过减少脂肪神经酰胺的产生减轻高胆固醇饮食诱导的动脉粥样硬化，降低胆固醇水平，减少炎症反应，导致改善血脂异常和动脉粥样硬化。Smpd3，编码中性鞘磷脂酶的基因，被鉴定为由参与神经酰胺生成的HIF-1α直接调控的新靶基因。在附睾脂肪组织中注射慢病毒-SMPD3逆转了脂肪细胞中神经酰胺的减少，并消除了脂肪细胞HIF-1α缺陷型小鼠动脉粥样硬化的改善。因此,抑制HIF-1α可能是减缓动脉粥样硬化进展的新方法。
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