Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis.
J Cell Biol
; 222(12)2023 12 04.
Article
en En
| MEDLINE
| ID: mdl-37787764
ABSTRACT
Sphingomyelin plays a key role in cellular cholesterol homeostasis by binding to and sequestering cholesterol in the plasma membrane. We discovered that synthesis of very long chain (VLC) sphingomyelins is inversely regulated by cellular cholesterol levels; acute cholesterol depletion elicited a rapid induction of VLC-sphingolipid synthesis, increased trafficking to the Golgi apparatus and plasma membrane, while cholesterol loading reduced VLC-sphingolipid synthesis. This sphingolipid-cholesterol metabolic axis is distinct from the sterol responsive element binding protein pathway as it requires ceramide synthase 2 (CerS2) activity, epidermal growth factor receptor signaling, and was unaffected by inhibition of protein translation. Depletion of VLC-ceramides reduced plasma membrane cholesterol content, reduced plasma membrane lipid packing, and unexpectedly resulted in the accumulation of cholesterol in the cytoplasmic leaflet of the lysosome membrane. This study establishes the existence of a cholesterol-sphingolipid regulatory axis that maintains plasma membrane lipid homeostasis via regulation of sphingomyelin synthesis and trafficking.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Esfingomielinas
/
Membrana Celular
/
Esfingosina N-Aciltransferasa
/
Membranas Intracelulares
Idioma:
En
Revista:
J Cell Biol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos