1). Ceramide is metabolized to sphingosine by ceramidases, which in turn is metabolized by sphingosine kinases to sphingosine-1-phosphate

(S1P). A host of cellular responses have been discovered for these three bioactive sphingolipids (e.g. cell senescence, differentiation, apoptosis and cell cycle arrest for ceramide; apoptosis and cell cycle arrest for sphingosine; and proliferation, mitogenesis, migration, angiogenesis, and protection from apoptosis for S1P). Reviews of sphingolipid metabolism, sphingolipid signaling, and the mechanisms of action of ceramide, sphingosine and S1P emphasize the complex web of interactions that occurs because of the intricately interconnected network of sphingolipid species and enzymes that

are involved.10,11 Lee et al.9 now show that in a mouse strain prone to gallstone formation, feeding a lithogenic diet is associated with GS-1101 cost elevated levels of ceramide in serum and bile. Furthermore, these ceramide levels are decreased by the addition of myoricin, a specific inhibitor of the first and rate-limiting step in the sphingolipid biosynthetic pathway catalyzed by SPT. After 6 weeks on the diets, 65% click here of mice on the lithogenic diet formed gallstones, compared with none in the control chow group and 15% in the lithogenic diet with myoricin group. Serum cholesterol and triglyceride levels were also elevated in the lithogenic diet group; these levels were reduced in the myoricin-treated mice. Gallbladder p38 mitogen-activated protein kinase phosphorylation was

increased in the lithogenic diet group, which was reduced with myoricin treatment. The findings reported are preliminary; the mechanisms by which inhibition of the sphingolipid biosynthetic pathway leads to cholesterol gallstone formation remain undefined. Nevertheless, medchemexpress based on the extensive literature that has accumulated with respect to cholesterol gallstone pathogenesis on the one hand, and bioactive sphingolipid biology on the other, one can create a roadmap for future studies that will likely yield mechanistic insights. One potential mechanism involves effects on gallbladder inflammation. Gallstone formation in mouse models involves activation of an inflammatory response.12 Bioactive sphingolipids are known to modulate inflammatory mediators.13 Therefore, one possible mechanism involves downregulation of inflammatory mediators in the gallbladder by inhibition of the de novo sphingolipid biosynthetic pathway. This scenario is supported by the findings of a previous study by the same group.14 A high-cholesterol diet fed to Syrian Golden hamsters induced gallstones in association with sixfold elevations of biliary ceramide and S1P. Levels of gallbladder inducible nitric oxide synthase and phosphorylated signal transducer and activator of transcription 3, which have been linked to inflammation, were increased.