Adenovirus-mediated expression of hepatic lipase in LCAT transgenic mice.
In order to evaluate the coordinate role that hepatic lipase (HL) and lecithin:cholesterol acyltransferase (LCAT) play in modulating HDL particle heterogeneity and function in vivo we utilized recombinant adenovirus to express HL in control and LCAT transgenic mice. Adenovirus-mediated expression of human HL in control (n = 4, LCAT activity = 42 +/- 1 nmol/ml per h) and LCAT-tg mice (n = 4, LCAT activity = 3566 +/- 93 nmol/ml per h) resulted in post heparin HL activities of 24,358 +/- 6080 and 27,266 +/- 7985 nmol/ml per min, respectively. Overexpression of HL led to significant reductions in total cholesterol, phospholipids, and HDL cholesterol in both LCAT-tg (62, 62, and 63%, P < 0.05) and control mice (68, 63, and 78%, P < 0.01) as well as to the formation of more homogenous HDL. However, compared to control animals, the reductions in the plasma concentrations of HDL-cholesterol and apoA-I were less in LCAT-tg mice (HDL-cholesterol: -62 +/- 15% vs. -78 +/- 15%, P = 0.18; apoA-I: -36 +/- 7% vs. -76 +/- 8%, P < 0.0005). Gel filtration analysis revealed that in LCAT-tg mice the apoE-rich HDL1 was preferentially reduced by expression of HL in vivo. Compared to control mice the reduction in the apoA-I/A-II HDL in transgenic mice was significantly less indicating that a subset of HDL in LCAT transgenic mice are resistant to the action of HL. These combined data support a role for both HL and LCAT in modulating HDL heterogeneity and function, properties which may ultimately affect the ability of LCAT transgenic mouse HDL to function in the process of reverse cholesterol transport.
Dugi
K A
KA
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Vaisman
B L
BL
Sakai
N
N
Knapper
C L
CL
Meyn
S M
SM
Brewer
H B
HB
Santamarina-Fojo
S
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008049:Lipase / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics*
D016632:Apolipoprotein A-I; D017931:DNA Primers; D008055:Lipids; D008075:Lipoproteins, HDL; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase