Abstract
Plasma cholesteryl ester (CE) synthesis by lecithin cholesterol acyltransferase (LCAT) is activated by apolipoprotein (apo)A-I. We studied the effect of plasma apoA-I concentration on LCAT activation, using normal, heterozygous or homozygous apoA-I-deficient mice made by gene targeting. Plasma esterified cholesterol concentrations of mice fed chow diets were ordered (mean +/- SEM): 105 +/- 7 (normal) > 70 +/- 5 (heterozygotes) > 26 +/- 2 (homozygotes) mg/dl. Plasma free cholesterol concentrations were similar among the three genotypes. Endogenous LCAT activity, 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 plasma. Using a recombinant exogenous substrate consisting of egg yolk phospholipid, [14C]cholesterol, and apoA-I, CE formation of normals and heterozygotes 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 vesicle substrate particle containing phospholipid and [14C]cholesterol, CE formation was ordered: 1.6 +/- 0.1 (normal) = 1.6 +/- 0.1 (heterozygotes) > 0.6 +/- 0.1 (homozygotes) nmol/h per ml plasma; addition of apoA-I to the plasma of homozygous animals restored CE formation to normal levels (1.6 +/- 0.1). CE fatty acid analysis demonstrated that plasma from homozygous mice contained significantly more saturated and monounsaturated and fewer polyunsaturated fatty acids compared to normal and heterozygous mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Highlights
* homozygous animals restored C E formation to normal levels (1.6 0.1)
IWe conclude that mice with no detectable plasma Apolipoprotein A-I (apoA-I) have marked reductions in plasma C E concentrations (70%) and cholesteryl ester (CE) synthesis (60%) and a more saturated plasma C E fatty acid profile, which likely reflects an increased hepatic contribution to the plasma C E pool
Previous studies have shown that total plasma and high density lipoproteins (HDL) cholesterol concentrations were significantly lower in heterozygous and homozygous apoA-I deficient mice compared to normal mice [24, 25]
Summary
C E fatty acid analysis demonstrated that plasma from homozygous mice contained significantly more saturated and monounsaturated and fewer polyunsaturated fatty acids compared to normal and heterozygous mice. IWe conclude that mice with no detectable plasma apoA-I have marked reductions in plasma C E concentrations (70%) and CE synthesis (60%) and a more saturated plasma C E fatty acid profile, which likely reflects an increased hepatic contribution to the plasma C E pool. The decreased plasma C E synthesis in homozygous apoA-I-deficient mice is primarily due to a deficiency in apoA-I activator protein, but is partly the result of a decrease in H D L substrate particles and LCAT enzyme activity. One half of the gene dosage of apoA-I in mice is sufficient for activation of plasma LCAT.-Parks, J.
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