Add time:09/07/2019         Source:sciencedirect.com

The biological activity of ceramide, an intermediate in the synthesis and catabolism of sphingolipids, has been shown to be mimicked by short-chain N-acyl analogues. A potential role for ceramide in modulating cholesterol esterification was investigated using a series of short-chain ceramides and dihydroceramides. Acyl-CoA:cholesterol acyltransferase (ACAT) in CHO cells was inhibited rapidly (< 30 min) and in a dose-dependent fashion by two N-acyl analogues of naturally occurring d-erythro-ceramide, N-acetyl-sphingosine (d-erythro-C2-ceramide) and N-hexanoyl-sphingosine (d-erythro-C6-ceramide). At 10 μM d-erythro-C2-ceramide, esterification of cholesterol was inhibited by 95% in CHO cells grown in delipidated serum, and 80–85% in cells grown in 25-hydroxycholesterol or human low-density lipoprotein (LDL). d-erythro-C2-Ceramide did not inhibit [14C]oleate-labelling of triacylglycerol and phospholipid. Inhibition of cholesterol esterification in cells and isolated membranes required the d-erythro (2S,3R) configuration (the l-threo isomer of C2-ceramide was not inhibitory) and an N-acyl group (sphingosine and sphinganine did not inhibit). dl-erythro-C2-Dihydroceramide was also a potent ACAT inhibitor in isolated membranes (IC50, 0.2 μM) and cells indicating lack of requirement for a 4-trans double bond. Consistent with results for C2-ceramides, dl-threo-C2-dihydroceramide was not inhibitory in cells or in vitro. Long-chain ceramide and N-palmitoyl-dihydroceramide did not inhibit ACAT in isolated membranes. Compared to d-erythro-C2-ceramide, d-erythro-C6- and C4-ceramide were slightly weaker inhibitors of ACAT in isolated membranes. Thus, N-acyl chain length could influence inhibition, either by altering the effective concentration of ceramide in membranes or affinity for the ACAT enzyme. Short-chain ceramides and dihydroceramides are the first ACAT inhibitors described with structural similarity to a naturally occurring compound.

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