The influence of apoE-deficiency and LDL-receptor-deficiency on the HDL subpopulation profile in mice and in humans.

Objective: As apoE(-/-) and LDL-Receptor(-/-) mice are commonly used in atherosclerosis research; our objective was to point out the differences in HDL metabolism between mice and humans regarding the roles of apoE and LDLR.

Methods: We examined HDL particles obtained from wild type (WT), LDLR(-/-), and apoE(-/-) mice, as well as from normal, homozygous familial hypercholesterolemic (FH), and apoE-deficient human subjects by 2-dimensional non-denaturing PAGE followed by immunoblot and image analysis.

Results: In WT mice, the majority of apoA-I was in large (9.0-12.0 nm), α-mobility HDL with trace amounts of apoA-I in small, preβ-1 HDL. In LDL(-/-) mice, both apoA-I- and apoE-containing HDL looked normal. About one-third of apoE was associated with large apoA-I-containing HDL (LpA-I:E) and two-thirds formed large HDL without apoA-I (LpE). In apoE(-/-) mice, apoA-I was detected in multiple, β-preβ-mobility, tightly-packed bands (7.0-13.0 nm) indicating that apoA-I in these animals was present only in poorly-lipidated, discoidal particles. Neither FH nor apoE-deficient humans showed significant alterations in apoA-I-containing HDL particles as compared to non-carriers.

Conclusions: Our data indicate that apoE is necessary for the formation of spherical, lipidated HDL particles in mice, but not in humans, probably because mice lack CETP. Based on our data, we hypothesize that apoE(-/-) mice have little or no functional HDL, therefore results from apoE(-/-) mice cannot be extrapolated to humans without taking this significant difference into consideration.