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 apolipoprotein (apo) A-I/C-III/A-IV gene cluster. This expression induced hyperlipidemia 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 examined 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 fat-high cholesterol diet up-regulates the intestinal expression of the three 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 showed a 65% reduction in diet-induced aortic lesions compared with non-Tg mice. Atherogenic diet increases the expression of the genes encoding the scavenger 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 increased reverse cholesterol transport is the basis of the protective mechanism observed in these animals. In conclusion, we present evidence that the expression of the human gene cluster in mice protects against atherogenesis in response to an atherogenic diet.
Baroukh
N
N
Unité d'Expression des Gènes Eucaryotes, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Ostos
M A
MA
Vergnes
L
L
Recalde
D
D
Staels
B
B
Fruchart
J
J
Ochoa
A
A
Castro
G
G
Zakin
M M
MM
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics*; D001056:Apolipoproteins C / Q000097:blood / Q000235:genetics*; D001161:Arteriosclerosis / Q000503:physiopathology*; D018955:CD36 Antigens / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D019076:Transgenes; D014280:Triglycerides / Q000097:blood; D014407:Tumor Cells, Cultured
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D018955:CD36 Antigens; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; C022205:apolipoprotein A-IV; D002784:Cholesterol