ORMDL proteins regulate ceramide levels during sterile inflammation

Journal of Lipid Research

Clement Oyeniran¹  Debolina D. Biswas²  Michael Maceyka²  Sheldon Milstien²  Sarah Spiegel²  Tomasz Kordula²  Jeremy Allegood²  Lin Cai³ 

[1] Department of Biochemistry and Molecular Biology and the Massey Cancer Center,Virginia Commonwealth University School of Medicine, Richmond, VA 23298;Department of Biochemistry and Molecular Biology and the Massey Cancer Center,Virginia Commonwealth University School of Medicine, Richmond, VA 23298;School of Pharmacy,Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;

关键词: serine palmitoyltransferase;    ORM-like protein;    ceramide synthase;    sphingolipids;   

DOI  :  

来源: DOAJ

【 摘 要 】

The bioactive sphingolipid metabolite, ceramide, regulates physiological processes important for inflammation and elevated levels of ceramide have been implicated in IL-1-mediated events. Although much has been learned about ceramide generation by activation of sphingomyelinases in response to IL-1, the contribution of the de novo pathway is not completely understood. Because yeast ORM1 and ORM2 proteins negatively regulate ceramide levels through inhibition of serine palmitoyltransferase, the first committed step in ceramide biosynthesis, we examined the functions of individual mammalian ORM orthologs, ORM (yeast)-like (ORMDL)1–3, in regulation of ceramide levels. In HepG2 liver cells, downregulation of ORMDL3 markedly increased the ceramide precursors, dihydrosphingosine and dihydroceramide, primarily from de novo biosynthesis based on [U-13C]palmitate incorporation into base-labeled and dual-labeled dihydroceramides, whereas downregulation of each isoform increased dihydroceramides [13C]labeled in only the amide-linked fatty acid. IL-1 and the IL-6 family cytokine, oncostatin M, increased dihydroceramide and ceramide levels in HepG2 cells and concomitantly decreased ORMDL proteins. Moreover, during irritant-induced sterile inflammation in mice leading to induction of the acute-phase response, which is dependent on IL-1, expression of ORMDL proteins in the liver was strongly downregulated and accompanied by increased ceramide levels in the liver and accumulation in the blood. Together, our results suggest that ORMDLs may be involved in regulation of ceramides during IL-1-mediated sterile inflammation.

【 授权许可】

Unknown