Functional Lecithin:Cholesterol Acyltransferase Deficiency and High Density Lipoprotein Deficiency in Transgenic Mice Overexpressing Human Apolipoprotein A-II

The concentration of high density lipoproteins (HDL) is inversely related to the risk of atherosclerosis. The two major protein components of HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of apoA-II in lipoprotein metabolism and atherosclerosis, we have developed three lines of C57...

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Published in:The Journal of biological chemistry 1996-03, Vol.271 (12), p.6720-6728
Main Authors: Marzal-Casacuberta, Africa, Blanco-Vaca, Francisco, Ishida, Brian Y., Julve-Gil, Josep, Shen, Jianhe, Calvet-Márquez, Santiago, González-Sastre, Francesc, Chan, Lawrence
Format: Article
Language:English
Subjects:
Animals
Apolipoprotein A-II - genetics
Cholesterol - blood
Cholesterol, Dietary - blood
Dietary Fats - administration & dosage
Humans
Lipoproteins, HDL - chemistry
Lipoproteins, HDL - drug effects
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Electron
Particle Size
Phenotype
Sterol O-Acyltransferase - blood
Sterol O-Acyltransferase - drug effects
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Summary:The concentration of high density lipoproteins (HDL) is inversely related to the risk of atherosclerosis. The two major protein components of HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of apoA-II in lipoprotein metabolism and atherosclerosis, we have developed three lines of C57BL/6 transgenic mice expressing human apoA-II (lines 25.3, 21.5, and 11.1). Northern blot experiments showed that human apoA-II mRNA was present only in the liver of transgenic mice. SDS-polyacrylamide gel electrophoresis and Western blot analysis demonstrated a 17.4-kDa human apoA-II in the HDL fraction of the plasma of transgenic mice. After 3 months on a regular chow, the plasma concentrations of human apoA-II were 21 ± 4 mg/dl in the 25.3 line, 51 ± 6 mg/dl in the 21.5 line, and 74 ± 4 mg/dl in the 11.1 line. The concentration of cholesterol in plasma was significantly lower in transgenic mice than in control mice because of a decrease in HDL cholesterol that was greatest in the line that expressed the most apoA-II (23 mg/dl in the 11.1 line versus 63 mg/dl in control mice). There was also a reduction in the plasma concentration of mouse apoA-I (32 ± 2, 56 ± 9, 91 ± 7, and 111 ± 2 mg/dl for lines 11.1, 21.5, 25.3, and control mice, respectively) that was inversely correlated with the amount of human apoA-II expressed. Additional changes in plasma lipid/lipoprotein profile noted in line 11.1 that expressed the highest level of human apoA-II include elevated triglyceride, increased proportion of total plasma, and HDL free cholesterol and a marked (>10-fold) reduction in mouse apoA-II. Total endogenous plasma lecithin:cholesterol acyltransferase (LCAT) activity was reduced to a level directly correlated with the degree of increased plasma human apoA-II in the transgenic lines. LCAT activity toward exogenous substrate was, however, only slightly decreased. The biochemical changes in the 11.1 line, which is markedly deficient in plasma apoA-I, an activator for LCAT, are reminiscent of those in patients with partial LCAT deficiency. Feeding the transgenic mice a high fat, high cholesterol diet maintained the mouse apoA-I concentration at a normal level (69 ± 14 mg/dl in line 11.1 compared with 71 ± 6 mg/dl in nontransgenic controls) and prevented the appearance of HDL deficiency. All this happened in the presence of a persistently high plasma human apoA-II (96 ± 14 mg/dl). Paradoxical HDL elevation by high fat diets has been observed in humans and is rep
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.271.12.6720