Hyperlipidemia of ApoE2(Arg(158)-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression.
To investigate the relative roles of the LDL receptor- and non-LDL receptor-mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg(158)-Cys) (apoE2) and apoE3-Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-/-.Ldlr-/- background, expression of neither apoE2 nor apoE3-Leiden results in a decrease of the hyperlipidemia. In contrast, serum cholesterol levels are increased by the introduction of apoE2 and apoE3-Leiden in Apoe-/-.Ldlr-/- mice (to 39.1+/-7.1 and 37.6+/-7.6 mmol/L, respectively, from 25. 9+/-6.5 mmol/L). In addition, in these transgenic mice, the serum triglyceride levels are substantially increased (to 9.6+/-7.0 and 5. 8+/-2.8 mmol/L, respectively, from 0.7+/-0.5 mmol/L), which is associated with a decreased efficiency of in vitro LPL-mediated lipolysis of circulating VLDL. The VLDL-triglyceride secretion rate is not affected by the expression of apoE2 or apoE3-Leiden on the Apoe-/-.Ldlr-/- background. These results indicate that in the absence of the LDL receptor, clearance of triglyceride-rich apoE2 and apoE3-Leiden-containing lipoproteins via alternative hepatic receptors, such as the LDL receptor-related protein (LRP) is inefficient. Although apoE2 and apoE3-Leiden are disturbed in binding to the LDL receptor in vitro, expression of 1 or 2 mouse Ldlr alleles in an apoE2.Apoe-/- or apoE3-Leiden.Apoe-/- background results in a gene dose-dependent decrease of the hyperlipidemia. Furthermore, overexpression of the LDL receptor via adenovirus-mediated gene transfer rescues the hyperlipidemia associated with apoE2 and apoE3-Leiden expression. These data indicate that in apoE2 and apoE3-Leiden transgenic mice, the LDL receptor constitutes the predominant route for clearance of VLDL remnants, carrying even poorly binding apoE variants, and that this pathway is functional despite an apoE-mediated disturbance in VLDL triglyceride lipolysis.
van Dijk
K W
KW
Department of Human Genetics, Leiden University Medical Center, The Netherlands. ko@ruly46.medfac.leidenuniv.nl
van Vlijmen
B J
BJ
de Winther
M P
MP
van 't Hof
B
B
van der Zee
A
A
van der Boom
H
H
Havekes
L M
LM
Hofker
M H
MH
D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics*; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017354:Point Mutation; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D011973:Receptors, LDL; D014280:Triglycerides