Fatty acid transport protein 2 interacts with ceramide synthase 2 to regulate ceramide synthesis

ABSTRACT: Dihydroceramide is generated via the action of (dihydro)ceramide synthases (CerSs), which use two substrates, namely sphinganine and fatty acyl CoAs. Sphinganine is generated via the sequential activity of two integral membrane proteins located in the endoplasmic reticulum. Less is known about the source of supply of the fatty acyl CoAs, although a number of cytosolic proteins in the pathways of acyl CoA generation have been shown to modulate ceramide synthesis via direct or indirect interaction with the CerSs. We now demonstrate, by proteomic analysis of immunoprecipitated proteins, that fatty acid transporter protein 2 (FATP2) (also known as very long-chain acyl-CoA synthetase) directly interacts with CerS2 in mouse liver. Studies in cultured cells demonstrated that other members of the FATP family can also interact with CerS2, with the interaction dependent on both proteins being catalytically active. Transfection of cells with FATP1, FATP2 or FATP4 increased ceramide levels although only FATP2 and 4 increased dihydroceramide levels, consistent with their known intracellular locations. Finally, lipofermata, an FATP2 inhibitor which is believed to directly impact tumor cell growth via modulation of FATP2, decreased de novo dihydroceramide synthesis, suggesting that some of the proposed therapeutic effects of lipofermata may actually be mediated via (dihydro)ceramide rather than directly via acyl CoA generation

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Meital Kupervaser  

LAB HEAD: Anthony H. Futerman

PROVIDER: PXD031088 | Pride | 2022-04-04

REPOSITORIES: Pride