Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Abstract

Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

Sphingosine‐1‐phosphate in mitochondrial function and metabolic diseases

“…230 SPHK modulators, S1PL modulators, and S1P scavengers have attracted much attention. 231 Using transgenic animals expressing fluorescently labeled S1PRs, SPHKs, and other sphingolipid-metabolic enzymes, the mechanism regulating these enzyme-receptor systems in vivo can be identified and utilized as a tool for future research. Nevertheless, these bioactive sphingolipid metabolites are rapidly transformed into each other and are intermediates in complex sphingolipid biosynthesis.…”

“…Studies have shown that the diverse biological effects of S1P mainly depend on the subtype of adaptor proteins and the specific expression of GPCRs in tissues 230 . SPHK modulators, S1PL modulators, and S1P scavengers have attracted much attention 231 . Using transgenic animals expressing fluorescently labeled S1PRs, SPHKs, and other sphingolipid‐metabolic enzymes, the mechanism regulating these enzyme‐receptor systems in vivo can be identified and utilized as a tool for future research.…”

FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

“…In blood, S1P exists as a complex with its protein carrier chaperones that include albumin, apolipoprotein M (ApoM), and ApoA4, which presents S1P to its cognate receptors (Blaho, 2020).…”