Monowarul Mobin Siddique, Ying Li, Bhagirath Chaurasia, Vincent A Kaddai, Scott A Summers

Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces ceramides, the fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Though ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these latter molecules accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation and the lipids are now implicated in the etiology, treatment, or diagnosis of diabetes, cancer, ischemia/reperfusion injury, and neurodegenerative diseases. This mini-review summarizes recent findings on this emerging class of bioactive lipids.