Role of endothelial lipase in plasma HDL levels in a murine model of hypertriglyceridemia.
OBJECTIVE
Hypertriglyceridemia is the most common cause of low plasma high-density lipoprotein cholesterol (HDL-C) levels; however, the correlation between high triglyceride (TG) and low HDL-C remains unclear. Endothelial lipase (EL) is a determinant of plasma HDL levels. We investigated the role of EL in HDL metabolism in a murine model of acute hypertriglyceridemia.


RESULTS
To establish TG-dominant hyperlipidemia, EL-/- and wild-type (WT) mice were injected with Poloxamer-407 (P-407, 0.5 g/kg, i.p.). A single injection of P-407 resulted in a marked increase in plasma TG and cholesterol levels together with a decrease in HDL-C levels. Although plasma TG levels were similar in EL-/- and WT mice after P-407 injection, HDL-C levels were 80% higher and the HDL particle size was significantly larger in EL-/- mice than in WT mice. P-407 treatment inhibited plasma lipoprotein lipase activity and EL phospholipase activity, without decreasing their expressions. Adenovirus-mediated overexpression of EL in the liver reduced plasma HDL-C levels in both normo- and hyperlipidemic mice, while overexpression of catalytically inactive EL reduced HDL-C levels in hyperlipidemic mice. Cell culture experiments revealed that both catalytically active and inactive EL promoted cellular HDL uptake to the same extent.


CONCLUSIONS
EL regulates plasma HDL levels in mice in the normolipidemic as well as the acute hypertriglyceridemic state. EL can modulate plasma HDL-CHOL levels through both its lipolytic and ligand-binding functions in hypertriglyceridemic mice, while lipolytic activity appears to be the main determinant for its effects on HDL metabolism in normolipidemic mice.
Tanaka
Hanayo
H
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Ishida
Tatsuro
T
Johnston
Thomas P
TP
Yasuda
Tomoyuki
T
Ueyama
Tomomi
T
Kojima
Yoko
Y
Kundu
Ramendra K
RK
Quertermous
Thomas
T
Ishikawa
Yuichi
Y
Hirata
Ken-Ichi
K
D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood*; D005079:Excipients; D015228:Hypertriglyceridemia / Q000097:blood / Q000201:enzymology* / Q000209:etiology; D008049:Lipase / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020442:Poloxamer / Q000008:administration & dosage / Q000494:pharmacology
D008076:Cholesterol, HDL; D005079:Excipients; D020442:Poloxamer; D008049:Lipase; C498741:Lipg protein, mouse