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.