Disruption of adipocyte HIF-1 α improves atherosclerosis through the inhibition of ceramide generation

Acta Pharm Sin B. 2022 Apr;12(4):1899-1912. doi: 10.1016/j.apsb.2021.10.001. Epub 2021 Oct 14.


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.

Keywords: 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.