RRC ID 78633
Author Kita N, Hamamoto A, Gowda SGB, Takatsu H, Nakayama K, Arita M, Hui SP, Shin HW.
Title Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis.
Journal J Lipid Res
Abstract Lipid transport is an essential cellular process with importance to human health, disease development, and therapeutic strategies. Type IV P-type ATPases (P4-ATPases) have been identified as membrane lipid flippases by utilizing nitrobenzoxadiazole (NBD)-labeled lipids as substrates. Among the 14 human type IV P-type ATPases, ATP10D was shown to flip NBD-glucosylceramide (GlcCer) across the plasma membrane. Here, we found that conversion of incorporated GlcCer (d18:1/12:0) to other sphingolipids is accelerated in cells exogenously expressing ATP10D but not its ATPase-deficient mutant. These findings suggest that 1) ATP10D flips unmodified GlcCer as well as NBD-GlcCer at the plasma membrane and 2) ATP10D can translocate extracellular GlcCer, which is subsequently converted to other metabolites. Notably, exogenous expression of ATP10D led to the reduction in cellular hexosylceramide levels. Moreover, the expression of GlcCer flippases, including ATP10D, also reduced cellular hexosylceramide levels in fibroblasts derived from patients with Gaucher disease, which is a lysosomal storage disorder with excess GlcCer accumulation. Our study highlights the contribution of ATP10D to the regulation of cellular GlcCer levels and maintaining lipid homeostasis.
Volume 65(3)
Pages 100508
Published 2024-3-1
DOI 10.1016/j.jlr.2024.100508
PII S0022-2275(24)00013-0
PMID 38280458
PMC PMC10910339
MeSH Adenosine Triphosphatases / metabolism Biological Transport Cell Membrane / metabolism Glucosylceramides* / metabolism Homeostasis Humans P-type ATPases* / metabolism
DNA material pCMV-VSV-G-RSV-Rev (RDB04393)