Dihydroceramides: From Bit Players to Lead Actors

Abstract

Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces 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. Although 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 dihydroceramides 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, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

“…Collectively, the above studies, together with those compiled in recent reviews (Rodriguez-Cuenca et al, 2014;Siddique et al, 2015), underscore the importance of dihydrosphingolipids in cell biology. Continued research on the biological function of these molecules may uncover novel therapeutic opportunities by modulating the Des1 enzyme.…”

“…In the following years, the number of publications dealing with the implication of dhCer in a multitude of physiological or pathological events has been continuously growing. The biological roles of dhCer have been recently examined in two excellent reviews (Rodriguez-Cuenca et al, 2014;Siddique et al, 2015).…”

Recent advances in the development of sphingosine kinase inhibitors

“…Regardless of the mode of Des1 inhibition, this inhibitory action reduces flux through the sphingolipid pathway, likely contributing to the previously observed decreases in cellular S1P caused by this agent, but most importantly results in substantial increases in dihydroceramides [52,68,82]. Since dihydroceramides can block ceramide-induced channel formation in membranes [83], increased intracellular levels can act to antagonise release of cytochrome C from mitochondria and attenuate apoptosis, while inducing cellular autophagy and leading to cell cycle arrest [84].…”

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…Ceramides are known for their structural role in plasma membranes and also as important signaling molecules involved in many essential cellular processes including inflammation, immune cell trafficking, vascular and epithelial integrity, apoptosis, autophagy, and stress responses (Maceyka & Spiegel, 2014). Their precursors, the dihydroceramides, which are transiently produced during de novo sphingolipid synthesis, are also emerging as important regulators of autophagy, hypoxia, and cellular proliferation, with biological functions that are distinct and nonoverlapping with those of the more prevalent ceramides (Siddique et al ., 2015). …”