The potential of sphingolipid depletion for the treatment of atherosclerosis

Abstract

Sphingolipids have been implicated as potential atherogenic lipids. Inhibition ofhepatic serine palmitoyl transferase (SPT) reduces plasma sphingomyelin (SM) levelsleading to a reduction of atherosclerosis in apolipoprotein-E gene knockout (apoE-/-)mice. In my thesis I have investigated the possibility that the reduced atherosclerosisresulting from SPT inhibition is associated with decreases in plasmaglycosphingolipids (GSL). Furthermore, I examined whether SPT inhibition can leadto regression of atherosclerotic lesions. This thesis shows the SPT inhibitor myriocininhibits atherosclerosis in apoE-/- mice fed a high fat diet. Lesion inhibition was mostpronounced at the aortic arch and distal sites of the thoracic and abdominal aorta.There was also a trend towards a reduction in lesion area at the aortic root. Myriocintreatment resulted in significant reductions in both plasma SM and GSLconcentrations. Moreover, it was demonstrated that myriocin significantly inhibitedthe progression of established atherosclerosis. Although the inhibition of lesionprogression was observed mainly in the distal regions of the aorta, regression of lesionsize was not detected. In addition, this thesis demonstrated for the first time thatselective inhibition of GSL synthesis by the GSL synthesis inhibitor, d-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (EtDO-P4) had nosignificant impact on lesion area in apoE-deficient mice. Thus, despite the previouslyobserved positive correlations between plasma and aortic GSL concentrations and thedevelopment of atherosclerosis, this thesis indicates that inhibition of GSL synthesisdoes not inhibit atherosclerosis in vivo. In other studies we assessed the possibilitythat myriocin may also be acting to increase hepatic apoA-I production via theinhibition of ERK phosphorylation. To address this, HepG2 cells and primary mousehepatocytes were treated with myriocin. This significantly increased apoA-I mRNA,and protein levels. It also increased apoA-I secrection, and decreased ERKphosphorylation. These in vitro data indicate that ERK phosphorylation plays a role inmodulating apoA-I expression, and that myriocin’s mechanism of action is linked tothis pathway. Overall, this thesis has expanded the current literature regarding the roleof sphingolipid synthesis inhibition and atherosclerosis