Human apoA-I/C-III/A-IV gene cluster transgenic rabbits: effects of a high-cholesterol diet.
We have generated transgenic rabbits that express the entire human apoA-I/C-III/A-IV gene cluster. As in humans, h-apoA-I and h-apoC-III were expressed in liver and intestine, whereas h-apoA-IV mRNA was detected in intestine only. Transgenic rabbits had significantly higher plasma total cholesterol, HDL-cholesterol and total phospholipid concentrations than non-transgenic littermates. In contrast to similar transgenic mice previously generated, which have gross hypertriglyceridemia, triglyceride concentrations were only moderately raised in transgenic rabbits. Plasma and HDL from transgenic rabbits were more effective than those from controls in promoting cholesterol efflux from cultured hepatoma cells. They had lower LCAT, lower CETP and higher PLTP activities than non-transgenic littermates. Cholesterol-feeding produced major increases in plasma lipids. The qualitative response to the diet was not modified by cluster expression. Human apoA-I concentration was halved by cholesterol-feeding, whereas h-apoC-III and h-apoA-IV concentrations were not significantly altered. Cholesterol efflux from hepatoma cells to plasma and HDL was not altered by the diet. Since lipoprotein metabolism of rabbits closely resembles that of humans, human apoA-I/C-III/A-IV transgenic rabbits may provide a reliable model for studies of the transcriptional regulation of the cluster, and for evaluating the effects of different agents on the expression of the three genes.
Unité d'Expression des Gènes Eucaryotes, Institut Pasteur, Paris, France.
Delia
D
Recalde
Nadine
N
Baroukh
Celine
C
Viglietta
Sonia
S
Prince
Julián
J
Verona
Laurent
L
Vergnes
Josette
J
Pidoux
M
M
Nazeem Nanjee
Fernando
F
Brites
Alberto
A
Ochoa
Graciela
G
Castro
Mario M
MM
Zakin
Norman E
NE
Miller
Louis
L
Marie Houdebine
D000821:Animal Feed; D000818:Animals; D030801:Animals, Genetically Modified; D016632:Apolipoprotein A-I / Q000235:genetics*; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A / Q000235:genetics*; D001056:Apolipoproteins C / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004032:Diet; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms; D051379:Mice; D005810:Multigene Family; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits
D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D002791:Cholesterol, Dietary; D012333:RNA, Messenger; C022205:apolipoprotein A-IV; D002784:Cholesterol