Overexpression of human apolipoprotein A-II in mice induces hypertriglyceridemia due to defective very low density lipoprotein hydrolysis.
Two lines of transgenic mice, hAIItg-delta and hAIItg-lambda, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent Vmax of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL.
Boisfer
E
E
Unité 505 INSERM, Institut des Cordeliers, 15, rue de l'Ecole de Médecine, 75006 Paris, France.
Lambert
G
G
Atger
V
V
Tran
N Q
NQ
Pastier
D
D
Benetollo
C
C
Trottier
J F
JF
Beaucamps
I
I
Antonucci
M
M
Laplaud
M
M
Griglio
S
S
Chambaz
J
J
Kalopissis
A D
AD
D000818:Animals; D016633:Apolipoprotein A-II / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics
D016633:Apolipoprotein A-II; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D020033:Protein Isoforms; D008071:Lipoprotein Lipase