Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond

Abstract

Given the multiple differences between mice and men, it was once thought that mice could not be used to model atherosclerosis, principally a human disease. Apolipoprotein E-deficient (apoEKO) mice have convincingly changed this view, and the ability to model human-like plaques in these mice has provided scientists a platform to study multiple facets of atherogenesis and to explore potential therapeutic interventions. In addition to its well-established role in lipoprotein metabolism, recent observations of reduced adiposity and improved glucose homeostasis in apoEKO mice suggest that apoE may also play a key role in energy metabolism in peripheral organs, including adipose tissue. Finally, along with apoEKO mice, knockin mice expressing human apoE isoforms in place of endogenous mouse apoE have provided insights into how quantitative and qualitative genetic alterations interact with the environment in the pathogenesis of complex human diseases.-Pendse, A. A., J. M. Arbones-Mainar, L. A. Johnson, M. K. Altenburg, and N. Maeda. Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond. J. Lipid Res. 2009. 50: S178-S182.Supplementary key words apolipoprotein E isoforms • diabetes • adipose tissue Apolipoprotein E (apoE) plays a central role in lipoprotein metabolism and is required for the efficient clearance of diet-derived chylomicrons and liver-derived VLDL remnants by the liver (1). Consequently, mice lacking apoE (apoEKO) provided the first practical model of hyperlipidemia and atherosclerosis. In this review, we revisit the primary features of lipoprotein metabolism and atherosclerosis in apoEKO mice and the contributions of human apoE isoforms using the apoE knock-in mice. We then extend our discussion to more recent observations that suggest an important role for apoE in peripheral energy metabolism and consequently in metabolic syndrome (MetS) and its components, mainly obesity and diabetes. LIPOPROTEIN METABOLISM IN APOEKO MICEPlasma cholesterol in wild-type mice on a regular chow diet is ?80 mg/dl, primarily carried in HDL particles. Mice have a small amount of LDL and other atherogenic lipoproteins, such as VLDL remnants. This high HDL-to-

Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway

“…Apo E plays a key role in lipoprotein metabolism by serving as a high-affinity ligand for the LDLR (29,30). Consistent with its important role in cholesterol homeostasis, apo E knockout mice develop hypercholesterolemia and spontaneous atherosclerosis (30).…”

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease

“…In contrast, there is a single Apoe gene in the mouse (10). To investigate the function of the polymorphic human APOE alleles, mice have been engineered so that the single murine Apoe gene has been replaced with the human APOE e2, e3, or e4 genes (10). Experiments have used both humanized APOE knockin mice, as well as Apoe-deficient mice, which are null for the murine Apoe gene, to investigate the role of apoE in lung disease.…”

“…As compared with the APOE e3 allele, the APOE e2 allele has minimal LDLR binding and results in type III hyperlipoproteinemia and accelerated atherosclerosis, whereas the APOE e4 allele has altered lipid binding that increases both plasma low-density lipoprotein and atherosclerosis risk. In contrast, there is a single Apoe gene in the mouse (10). To investigate the function of the polymorphic human APOE alleles, mice have been engineered so that the single murine Apoe gene has been replaced with the human APOE e2, e3, or e4 genes (10).…”

Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall

“…Human apoE, in contrast to other species, exists in one of three major isoforms, designated E2, E3, and E4. Each of these isoforms exhibit isoform-specific effects on atherosclerosis and Alzheimerʼs disease (1,2).…”