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.
Highlights
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
We extend our discussion to more recent observations that suggest an important role for Apolipoprotein E (apoE) in peripheral energy metabolism and in metabolic syndrome (MetS) and its components, mainly obesity and diabetes
Atherosclerosis is not a distinguishing feature described in apoE-deficient humans [10], apoE deficiency alone proved to be sufficient for aortic atherosclerotic plaques to develop in mice
Summary
Plasma 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-toLDL ratio is maintained even when mice are fed diets similar to those consumed by humans in Western society. This is in marked contrast with humans who carry the majority of their plasma cholesterol in LDL (110 mg/dl) [2]. Humans lacking apoE are reported to have elevated remnant cholesterol in plasma [10] Similar to these individuals, apoEKO mice accumulate cholesterol-rich remnant particles with plasma cholesterol levels reaching 400 mg/dl, even when fed a regular low-fat, low-cholesterol diet
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