Physiological variations in plasma sphingomyelin (SM) inversely correlate with lecithin‐cholesterol acyltransferase (LCAT) activity

Abstract

We previously showed that sphingomyelin (SM), the second most abundant phospholipid in plasma, inhibits lecithin‐cholesterol acyltransferase (LCAT), the enzyme activity critical for HDL maturation, partly by competing with its substrate, phosphatidylcholine (PC). The physiological relevance of this inhibition, however, has not been investigated. In this study, using plasma from various genetic models of mice with naturally varying ratios of SM/PC, we show that this ratio is inversely correlated with the rate of cholesterol esterification by LCAT. Mice deficient in serine palmitoyltransferase, or SM synthase, both of which have reduced SM/PC ratios, showed significantly higher than normal LCAT activity when assayed with the endogenous substrates. On the other hand, LDL receptor deficient mice, and apo E knockout mice, both of which have high SM/PC ratios, had lower than normal LCAT activities. The enzyme levels in plasma, as assayed with an exogenous substrate, were not significantly different, except for a small decrease in apo E knockout mice. Plasma samples with high SM/PC ratios had lower percentage of 20:4, 22:5, and 22:6 cholesteryl esters (CE), and higher percentage of 18:1CE, showing that in vivo, the contribution of LCAT to plasma CE is diminished while that of liver ACAT is enhanced. These results show that plasma SM is a physiological modulator of cholesterol esterification and plasma CE composition.