Metabolic pathways involved in the production of endogenous ceramide. Endogenous ceramide is produced via 2 main mechanisms: a catabolic pathway, involving the hydrolysis of the membrane lipid sphingomyelin by endosomal acidic and membrane-bound neutral SMases; and de novo synthesis. TNF-α can increase cellular ceramide via both mechanisms. The rise in ceramide can create a positive feedback loop to amplify ceramide production further via the activation of SMases. Once generated, ceramide can transiently accumulate within the cell or be converted into various metabolites such as sphingosine and sphingosine-1-phosphate. Cell responses to ceramide will therefore depend on the engagement of downstream effectors, the cell microenvironment and concomitant activation of enzymes that convert ceramide into other metabolites. CoA, coenzyme A; ER, endoplasmic reticulum; SMase, sphingomyelinase; TNF, tumour necrosis factor.
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