Inhibition of Endothelial Lipase Activity by Sphingomyelin in the Lipoproteins

Abstract

Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL, compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/ phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.

Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins

“…Furthermore, while it is known that HL acts preferentially on HDL compared to VLDL and LDL [4], the reason for this specificity is unknown, since it does not require an apoprotein cofactor for its activity. Our previous studies showed that sphingomyelin, the most abundant sphingolipid in the plasma lipoproteins, is an inhibitor of several lipolytic enzymes, including LCAT [9], secretory phospholipases II, V, and X [10,11], as well as endothelial lipase [12]. Since SM/PC ratio is lower in HDL than in VLDL or LDL [9], it is possible that SM also inhibits HL activity on lipoproteins, and this could explain its differential effects on lipoproteins.…”

Association of maternal prepregnancy BMI with metabolomic profile across gestation

“…38 It could be speculated that SM or ceramides, 280 intermediate products of SM biosynthesis, may contribute to the development of insulin resistance in 281 obese pregnant women and thus contribute to elevated glucose and insulin supply to the placenta and the 282 fetus. However, the relation of SM to pBMI only occurs in the first trimester and disappears with 283 advancing gestation.…”

Enhanced incorporation of dietary DHA into lymph phospholipids by altering its molecular carrier

“…While we have not determined the position occupied by DHA in the lymph PC, LPC-DHA could be generated from either sn-1 DHA PC or sn-2 DHA PC in the plasma compartment. Thus, the various PLA 1 activities like those of endothelial lipase [17,18], hepatic lipase [19], or LCAT [20,21] could generate LPC-DHA from sn-2 DHA PC, whereas the secretory phospholipases A 2 [28,29] could generate LPC-DHA from sn-1 DHA PC. The relative importance of various phospholipase activities of plasma in the generation of LPC-DHA in plasma is not yet known.…”

“…It has been reported that the intestinal HDL is also directly secreted into the plasma, rather than into the lymph [36], in which case the actual amount of DHA incorporated into HDL phospholipids may be much higher than reported here, because we only analyzed the HDL in the lymph. HDL PC is the preferred substrate for all enzymes displaying phospholipase activity in the plasma [18–20,28,29], and therefore the presence of DHA PC in HDL would be beneficial for the generation of LPC-DHA in the plasma compartment and for its potential uptake by the brain through the Mfsd2a [8] pathway. The amount of HDL secreted by the intestine can be increased significantly by LXR agonists which stimulate the transcription of ABCA1 [37].…”

“…Furthermore the PC generated in the intestine may be incorporated into HDL either directly by assembly in the mucosal cells [15] or due to a transfer of surface components from the chylomicrons during lipolysis by the lipoprotein lipase [16]. The PC from HDL may be hydrolyzed to LPC containing DHA either by the action(s) of endothelial lipase [17,18], hepatic lipase [19], or LCAT [20,21] and thus has a greater potential to cross the BBB. As a first step in testing these hypotheses we investigated the intestinal absorption of two molecular forms of DHA incorporated into micelle by rats with lymph duct cannulation.…”