{Reference Type}: Journal Article
{Title}: Disruption of adipocyte HIF-1α improves atherosclerosis through the inhibition of ceramide generation.
{Author}: Wang P;Zeng G;Yan Y;Zhang SY;Dong Y;Zhang Y;Zhang X;Liu H;Zhang Z;Jiang C;Pang Y;Wang P;Zeng G;Yan Y;Zhang SY;Dong Y;Zhang Y;Zhang X;Liu H;Zhang Z;Jiang C;Pang Y;
{Journal}: Acta Pharm Sin B
{Volume}: 12
{Issue}: 4
{Year}: Apr 2022
{Factor}: 14.903
{DOI}: 10.1016/j.apsb.2021.10.001
{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.