Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases

Luisa Rubinelli, Onorina Laura Manzo, Jin Sungho, Ilaria Del Gaudio, Rohan Bareja, Alice Marino, Sailesh Palikhe, Vittoria Di Mauro, Mariarosaria Bucci, Domenick J. Falcone, Olivier Elemento, Baran Ersoy, Sabrina Diano, Linda Sasset and Annarita Di Lorenzo ()
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Luisa Rubinelli: Weill Cornell Medicine
Onorina Laura Manzo: Weill Cornell Medicine
Jin Sungho: Columbia University Irving Medical Center
Ilaria Del Gaudio: Weill Cornell Medicine
Rohan Bareja: Weill Cornell Medicine and New York-Presbyterian Hospital
Alice Marino: Weill Cornell Medicine
Sailesh Palikhe: Weill Cornell Medicine
Vittoria Di Mauro: Weill Cornell Medicine
Mariarosaria Bucci: University of Naples Federico II
Domenick J. Falcone: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine and New York-Presbyterian Hospital
Baran Ersoy: Weill Cornell Medicine
Sabrina Diano: Columbia University Irving Medical Center
Linda Sasset: Weill Cornell Medicine
Annarita Di Lorenzo: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Accrual of ceramides, membrane and bioactive sphingolipids, has been implicated in endothelial dysfunction preceding cardiometabolic diseases. Yet, direct in vivo evidence, underlying mechanisms, and pathological implications are lacking. Here we show that suppression of ceramides and sphingosine-1-phosphate (S1P), a product of ceramide degradation, are causally linked to endothelial dysfunction and activation, contributing to vascular and metabolic disorders in high fat diet fed (HFD) male mice. Mechanistically, the upregulation of Nogo-B and ORMDL proteins suppress ceramide de novo biosynthesis in endothelial cells (EC) of HFD mice, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restore sphingolipid signaling and functions, lowers hypertension, and hepatic glucose production in HFD. Our results demonstrate in vivo that ceramide and S1P suppression rather than accrual contributes to endothelial dysfunction and cardiometabolic diseases in HFD mice. Our study also sets a framework for the development of therapeutic strategies to treat these conditions

Date: 2025
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DOI: 10.1038/s41467-025-56869-9

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