Joulia, E.; Ashley, E. L.; Tseng, P.; Arechiga, C.; Liang, Y.; Laguerre, A.; Ruchhoeft, M. L.; Rainaldi, J.; Handzlik, M. K.; Fallon, R. J.; Kim, H. Y.; Mali, P.; Brenner, D. A.; Kisseleva, T.; Zheng, Y.; Gantner, M. L.; Metallo, C. M.

Serine and glycine are altered in patients with metabolic disorders, and this dysregulation can lead to diverse pathologies. Modulation of serine levels via diet can influence relevant phenotypes in mouse models of metabolic syndrome. Here we identify serine dehydratase (Sds), a gluconeogenic hepatic enzyme involved in serine and threonine catabolism, as a key regulator of systemic serine and sphingolipid metabolism. We show that SDS is expressed and active in human liver tissue. Furthermore, Sds abundance strongly correlates with hepatic serine. This enzyme is highly active in BKS-db/db mice, which show amino acid alterations reminiscent of type 2 diabetes. Hepatic Sds overexpression increases serine and threonine degradation and promotes the accumulation of toxic 1-deoxysphingolipids (doxSLs). Conversely, Sds deletion dramatically increases systemic serine, glycine, and threonine while altering canonical and non-canonical sphingolipids. Finally, Sds deletion in BKS-db/db mice reduces skin doxSLs and accelerates wound healing. Our results demonstrate that Sds constrains serine levels in circulation and suggest therapeutic approaches for targeting this enzyme to improve chronic disorders.