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 reproduced in human
apoA-II overexpressing transgenic mice but not in control mice. Finally, HDL size and morphology varied substantially in the three transgenic lines, indicating the importance of
apoA-II concentration in the modulation of HDL formation. The LCAT and HDL deficiencies observed in this study indicate that
apoA-II plays a dynamic role in the regulation of plasma HDL metabolism.