Transcriptomics

Dataset Information

0

Suppression of endothelial ceramide de novo biosynthesis contributes to cardiometabolic diseases


ABSTRACT: Metabolic disorders and obesity increase the risk for cardiovascular (CV) disease, including hypertension, atherosclerosis, and myocardial infarction. Systemic endothelial dysfunction, a well-established response to CV risk factors, precedes the development of CV diseases. However, growing evidence suggest that endothelial dysregulation also contributes to metabolic disorders, underlying a centric role of the endothelium in cardiometabolic diseases. The accrual of the sphingolipid ceramide, bioactive molecule, has been causally implicated in endothelial dysfunction in vitro. However, direct in vivo evidence supporting the accrual of ceramide in the endothelium, underlying mechanisms, and pathological implications are lacking. Here, we showed that the suppression rather than the accrual of ceramides is causally linked to endothelial dysfunction, and imparts a pro-inflammatory and pro-atherosclerotic phenotype, contributing to both vascular and metabolic disorders. Mechanistically, the upregulation of Nogo-B and ORMDLs proteins, inhibitors of the first and rate limiting enzyme of the de novo biosynthesis, in the endothelium of obese and diabetic mice suppresses sphingolipid signaling, particularly ceramides and sphingosine-1-phosphate, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restores sphingolipid signaling and functions of the endothelium, improves hypertension and lowers hepatic glucose production. Our results demonstrating that Nogo-B-mediated suppression of sphingolipid metabolism and signaling in the endothelium has pathological implication in cardiometabolic disorders and set a framework for the development of therapeutic strategies to treat these conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE278555 | GEO | 2025/01/24

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2024-02-12 | GSE254426 | GEO
2020-01-30 | GSE132056 | GEO
2021-01-01 | GSE148498 | GEO
2023-10-24 | PXD044586 | Pride
2016-07-24 | E-GEOD-59719 | biostudies-arrayexpress
2024-01-01 | GSE243100 | GEO
| PRJNA1167768 | ENA
2021-11-02 | PXD026980 | Pride
2016-07-24 | GSE59719 | GEO
2022-05-08 | PXD032723 | Pride