Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-I(Milano).
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-IM), 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-IM carriers appear to be protected from the pro-atherogenic effect of a low HDL, transgenic mice expressing apo A-IM were generated. Mice expressing either wild-type human apo A-I or apo A-IM, together with human apo A-II, were crossed into mice lacking murine apo A-I. Apo A-IM/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-IM 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-IM in a mouse model reproduces the major lipid/lipoprotein abnormalities observed in human carriers. Thus, apo A-IM transgenic mice appear to be a suitable model in which to assess whether the mutation has an anti-atherogenic effect.
Chiesa
G
G
Center E. Grossi Paoletti, Institute of Pharmacological Sciences, University of Milan, Italy.
Stoltzfus
L J
LJ
Michelagnoli
S
S
Bielicki
J K
JK
Santi
M
M
Forte
T M
TM
Sirtori
C R
CR
Franceschini
G
G
Rubin
E M
EM
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics; D016633:Apolipoprotein A-II / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D014280:Triglycerides / Q000097:blood*
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; D014280:Triglycerides; C080631:apolipoprotein A-I Milano