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

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. Graphical abstract Adipocyte-HIF-1α increases ceramide levels through activation of Smpd3. SMPD3 lentivirus overexpression and ceramide administration reverse the improvements of adipocyte HIF-1α deficiency in atherosclerosis. The HIF-1α inhibitor PX-478 plays a protective role in atherosclerosis.Image 1

SUBMITTER: Wang P 

PROVIDER: S-EPMC9279628 | biostudies-literature |

REPOSITORIES: biostudies-literature