Esterification of 4β-hydroxycholesterol and other oxysterols in human plasma occurs independently of LCAT

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4 beta-hydroxycholesterol (4 beta HC), 0.38; 5,6 alpha-epoxycholesterol (5,6 alpha EC), 0.46; 5,6 beta-epoxycholesterol (5,6 beta EC), 0.51; cholesterol, 0.70; cholestane-3 beta,5 alpha,6 beta-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7 alpha-hydroxycholesterol (7 alpha HC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6 alpha EC, 5,6 beta EC, CT, 7 alpha HC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7 alpha HC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4 beta HC, 5,6 alpha EC, 7 alpha HC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4 beta HC. Substantial FA esterification of 4 beta HC, 5,6 alpha EC, 7 alpha HC, 7KC, and 27HC is independent of LCAT.