ORMDL in metabolic health and disease.

Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated fatty acids are substrates for serine palmitoyltransferase (SPT) the rate-limiting step in de novo sphingolipid biosynthesis. The mammalian orosomucoid-like protein isoforms ORMDL1-3 negatively regulate SPT activity. Here we summarize evidence that dysregulation of sphingolipid metabolism and SPT activity correlates with pathogenesis of obesity. This review also discusses the current understanding of the function of SPT and ORMDL in obesity and metabolic disease. Gaps and limitations in current knowledge are highlighted together with the need to further understand how ORMDL3, which has been identified as an obesity-related gene, contributes to the pathogenesis of obesity and development of metabolic disease related to its physiological functions. Finally, we point out the needs to move this young field of research forward.