Overexpression of low density lipoprotein receptor eliminates apolipoprotein B100-containing lipoproteins from circulation and markedly prevents early atherogenesis in apolipoprotein E-deficient mice.
Apolipoprotein E (ApoE) plays a pivotal role in the metabolism of apolipoprotein B (apoB)-containing lipoproteins. The defective apoE gene in humans can cause elevated plasma levels of apoB-containing lipoproteins such as chylomicron remnant and intermediate density lipoprotein (IDL). In this study, we examined whether liver-selective high-level expression of low-density lipoprotein receptor (LDLR) could affect the lipoprotein profile and atherogenesis in apoE-deficient (apoE-/-) mice. ApoE knockout mice expressing LDLR transgene in liver [apoE-/-;Tg(LDLR+/-)] were prepared after mating apoE-/- mice with the human LDLR transgenic mice. The apoE-/-;Tg(LDLR+/-) and littermate apoE-/- mice were fed a normal diet and sacrificed at 18 weeks of age. (1) The plasma levels of cholesterol and triglyceride in apoE-/-;Tg(LDLR+/-) mice were 51 and 33% lower than those of apoE-/- mice, respectively. (2) In the plasma of apoE-/-;Tg(LDLR+/-) mice, the levels of apoB-containing lipoprotein were reduced and apoB100-containg particles were totally eliminated. (3) By histochemical analysis, apoE-/-;Tg(LDLR+/-) mice showed drastic suppression of early atherogenesis; the lesion area of these mice was 1/70 of that in the littermate apoE-/- mice. These results indicate that, even in apoE-defective subjects, induction of hepatic LDLR expression could protect from early atherogenesis.
Murayama
T
T
Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, Japan.
Yokode
M
M
Horiuchi
H
H
Yoshida
H
H
Sano
H
H
Kita
T
T
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D011973:Receptors, LDL