FUNCTIONAL LECITHIN, CHOLESTEROL ACYLTRANSFERASE DEFICIENCY AND HIGH-DENSITY-LIPOPROTEIN DEFICIENCY IN TRANSGENIC MICE OVEREXPRESSING HUMANAPOLIPOPROTEIN A-II

The concentration of high density lipoproteins (HDL) is inversely rela ted to the risk of atherosclerosis, The two major protein components o f HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of a poA-II in lipoprotein metabolism and atherosclerosis, we have develope d three lines of C57BL/6 transgenic mice expressing human apoA-II (lin es 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-pol yacrylamide gel electrophoresis and Western blot analysis demonstrated a 17.4-kDa human apoA-II in the HDL fraction of the plasma of transge nic 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 concentrati on of cholesterol in plasma was significantly lower in transgenic mice than in control mice because of a decrease in HDL cholesterol that wa s greatest in the Line that expressed the most apoA-II (23 mg/dl in th e 11.1 line versus 63 mg/dl in control mice). There was also a reducti on 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 mi ce, respectively) that was inversely correlated with the amount of hum an apoA-II expressed, Additional changes in plasma lipid/lipoprotein p rofile noted in line 11.1 that expressed the highest level of human ap oA-II include elevated triglyceride, increased proportion of total pla sma, and RDL free cholesterol and a marked (>10-fold) reduction in mou se apoA-II. Total endogenous plasma lecithin:cholesterol acyltransfera se (LCAT) activity was reduced to a level directly correlated with the degree of increased plasma human apoA-II in the transgenic lines, LCA T activity toward erogenous substrate was, however, only slightly decr eased, The biochemical changes in the 11.1 line, which is markedly def icient in plasma apoA-I, an activator for LCAT, are reminiscent of tho se in patients with partial LCAT deficiency, Feeding the transgenic mi ce a high fat, high cholesterol diet maintained the mouse apoA-I conce ntration at a normal level (69 +/- 14 mg/dl in line 11.1 compared with 71 +/- 6 mg/dl in non-transgenic controls) and prevented the appearan ce of HDL deficiency, All this happened in the presence of a persisten tly high plasma human apoA-II (96 +/- 14 mg/dl), Paradoxical HDL eleva tion by high fat diets has been observed in humans and is reproduced i n human apoA-II overexpressing transgenic mice but not in control mice . Finally, HDL size and morphology varied substantially in the three t ransgenic lines, indicating the importance of apoA-II concentration in the modulation of HDL formation, The LCAT and HDL deficiencies observ ed in this study indicate that apoA-II plays a dynamic role in the reg ulation of plasma HDL metabolism.