Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-IMilano

In general, plasma concentrations of high density lipoproteins (HDL) are inversely related to the incidence of coronary artery disease. One exception to this trend is individuals with apolipoprotein A-I-Milano (apo A-I-M), a molecular variant of apo A-I, which results in very low plasma apo A-I and HDL-cholesterol levels. Despite these low levels, and other lipoprotein defects, individuals with this mutation have no increased risk for cardiovascular disease. As a first step in proving why apo A-I-M carriers appear to be protected from the pro-atherogenic effect of a low HDL, transgenic mice expressing apo A-I-M were generated. Mice expressing either wild-type human apo A-I or apo A-I-M, together with human apo A-II, were crossed into mice lacking murine apo A-I. Apo A-I-M/A-II mice had lower cholesterol and HDL plasma levels compared to apo A-I/A-II mice. Moreover, as in human carriers, apo A-I-M mice were characterized by elevated triglyceride plasma levels and by the presence of a population of very small HDL particles. These results indicate that the expression of apo A-I-M in a mouse model reproduces the major lipid/lipoprotein abnormalities observed in human carriers. Thus, apo A-I-M transgenic mice appear to be a suitable model in which to assess whether the mutation has an anti-atherogenic effect. (C) 1998 Elsevier Science Ireland Ltd.