Js. Parks et al., EFFECT OF APOLIPOPROTEIN-A-I DEFICIENCY ON LECITHIN-CHOLESTEROL ACYLTRANSFERASE ACTIVATION IN MOUSE PLASMA, Journal of lipid research, 36(2), 1995, pp. 349-355
Plasma cholesteryl ester (CE) synthesis by lecithin cholesterol acyltr
ansferase (LCAT) is activated by apolipoprotein (apo)A-I. We studied t
he effect of plasma apoA-I concen tration on LCAT activation, using no
rmal, heterozygous or homozygous apoA-I-deficient mice made by gene ta
rgeting. Plasma esterified cholesterol concentrations of mice fed chow
diets were ordered (mean +/- SEM): 105 +/- 7 (normal)>70 +/- 5 (heter
ozygotes) > 26 +/- 2 (homozygotes) mg/dl. Plasma free cholesterol conc
entrations were similar among the three genotypes. Endogenous LCAT act
ivity, measured as the decrease in plasma free cholesterol after a 1 h
incubation at 37 degrees C, was ordered: 44 +/- 3 (normal) > 21 +/- 2
(heterozygotes) > 5 +/- 1 (homozygotes) nmol CE formed/h per ml plasm
a. Using a recombinant exogenous substrate consisting of egg yolk phos
pholipid, [C-14]cholesterol, and apoA-I, CE formation of normals and h
eterozygotes was similar (27.4 +/- 0.6 and 28.8 +/- 1.3 nmol/h per ml
plasma, respectively), but was significantly less for homozygotes (19.
2 +/- 1.7 nmol/h per ml plasma). However, using a small unilamellar ve
sicle substrate particle containing phospholipid and [C-14]cholesterol
, CE formation was ordered: 1.6 +/- 0.1 (normal) = 1.6 +/- 0.1 (hetero
zygotes) > 0.6 +/- 0.1(homozygotes) nmol/h per ml plasma; addition of
apoA-I to the plasma of homozygous animals restored CE formation to no
rmal levels (1.6 +/- 0.1). CE fatty acid analysis demonstrated that pl
asma from homozygous mice contained significantly more saturated and m
onounsaturated and fewer polyunsaturated fatty acids compared to norma
l and heterozygous mice. We conclude that mice with no detectable plas
ma apoA-I have marked reductions in plasma CE: concentrations (70%) an
d CE synthesis (60%) and a more saturated plasma CE fatty acid profile
, which likely reflects an increased hepatic contribution to the plasm
a CE pool. The decreased plasma CE synthesis in homozygous apoA-I-defi
cient mice is primarily due to a deficiency in apoA-I activator protei
n, but is also partly the result of a decrease in HDL substrate partic
les and LCAT enzyme activity. In addition, one half of the gene dosage
of apoA-I in mice is sufficient for activation of plasma LCAT.