Expression of human apolipoprotein A-I/C-III/A-IV gene cluster in mice reduces atherogenesis in response to a high fat-high cholesterol diet

We have previously generated transgenic (Tg) mice expressing the human apol ipoprotein (apo) A-I/C-IIIIA-IV gene cluster. This expression induced hyper lipidemia but reduced atherosclerotic lesions in genetically modified mice lacking apoE. Atherosclerosis is a multifactorial process and environmental factors such as diet play significant roles in its development. We examine d here how an atherogenic diet influences the expression of the human genes and the characteristics of the Tg mice. Our results indicate that a high f at-high cholesterol diet up-regulates the intestinal expression of the thre e genes and the concentration of the three proteins in plasma. Cholesterol concentration was highly increased in the non-high density lipoprotein (HDL ) fraction, and less, although significantly, in the HDL fraction. Tgs show ed a 65% reduction in diet-induced aortic lesions compared with non-Tg mice . Atherogenic diet increases the expression of the genes encoding the scave nger receptor class B type I (SR-BI) and ATP binding cassette transporter 1 (ABCA1) proteins. As cholesterol efflux mediated by SR-BI or by ABCA1 was enhanced in Tg mice fed an atherogenic diet, we can hypothesize that increa sed reverse cholesterol transport is the basis of the protective mechanism observed in these animals. In conclusion, we present evidence that the expr ession of the human gene cluster in mice protects against atherogenesis in response to an atherogenic diet. (C) 2001 Federation of European Biochemica l Societies. Published by Elsevier Science B.V. All rights reserved.