The orosomucoid-like (ORMDL) protein family is involved in the regulation of de novo @entity8483 synthesis, @entity460 homeostasis, and unfolded protein response. Single nucleotide polymorphisms (SNPs) that increase @entity36709 expression have been associated with various immune/inflammatory diseases, although the pathophysiological mechanisms underlying this association are poorly understood. ORMDL proteins are claimed to be inhibitors of the @entity563 palmitoyltransferase (SPT). However, it is not clear whether individual ORMDL expression levels have an impact on @entity2367 synthesis. The present study addressed the interaction with and regulation of SPT activity by ORMDLs to clarify their pathophysiological relevance. We have measured @entity2367 production in HEK293 cells incubated with @entity2365 as a direct substrate for SPT reaction. Our results showed that a coordinated overexpression of the three isoforms inhibits the enzyme completely, whereas individual ORMDLs are not as effective. Immunoprecipitation and fluorescence resonance energy transfer (FRET) studies showed that @entity1 ORMDLs form oligomeric complexes that change conformation depending on cellular @entity8483 levels. Finally, using macrophages as a model, we demonstrate that @entity1 cells modify ORMDL genes expression levels coordinately to regulate the de novo @entity2367 synthesis pathway. In conclusion, we have shown a physiological modulation of SPT activity by general ORMDL expression level regulation. Moreover, because single @entity36709 protein alteration produces an incomplete inhibition of SPT activity, this work argues against the idea that @entity36709 pathophysiology could be explained by a simple on/off mechanism on SPT activity.

Coordinated Regulation of the Orosomucoid-like Gene Family Expression Controls de Novo XXXX Synthesis in @entity1 Cells.

@entity1 :: ('9606', 'Species') :: ['mammalian'] @entity2365 :: ('CHEBI:7896', 'Chemical') :: ['palmitate'] @entity2367 :: ('CHEBI:17761', 'Chemical') :: ['ceramide'] @entity36709 :: ('94103', 'Gene') :: ['ORMDL3'] @entity460 :: ('MESH:D002118', 'Chemical') :: ['calcium'] @entity563 :: ('CHEBI:17822', 'Chemical') :: ['serine'] @entity8483 :: ('CHEBI:26739', 'Chemical') :: ['sphingolipid']
@entity2367 :: (CHEBI:17761,Chemical) :: ['Ceramide']
