A Comparison of the Mouse and Human Lipoproteome: Suitability of the Mouse Model for Studies of Human Lipoproteins

Plasma
levels of low density lipoproteins (LDL) and high density
lipoproteins (HDL) exhibit opposing associations with cardiovascular
disease in human populations and mouse models have been heavily used
to derive a mechanistic understanding of these relationships. In humans,
recent mass spectrometry studies have revealed that the plasma lipoproteome
is significantly more complex than originally appreciated. This is
particularly true for HDL which contains some 90 distinct proteins,
a majority of which play functional roles that go beyond those expected
for simple lipid transport. Unfortunately, the mouse lipoproteome
remains largely uncharacterizeda significant gap given the
heavy reliance on the model. Using a gel filtration chromatography
and mass spectrometry analysis that targets phospholipid-bound plasma
proteins, we compared the mouse lipoproteome and its size distribution
to a previous, identical human analysis. We identified 113 lipid associated
proteins in the mouse. In general, the protein diversity in the LDL
and HDL size ranges was similar in mice versus humans, though some
distinct differences were noted. For the majority of proteins, the
size distributions, that is, whether a given protein was associated
with large versus small HDL particles, for example, were also similar
between species. Again, however, there were clear differences exhibited
by a minority of proteins that may reflect metabolic differences between
species. Finally, by correlating the lipid and protein size profiles,
we identified five proteins that closely track with the major HDL
protein, apolipoprotein A-I across both species. Thus, mice have most
of the minor proteins identified in human lipoproteins that play key
roles in inflammation, innate immunity, proteolysis and its inhibition,
and vitamin transport. This provides support for the continued use
of the mouse as a model for many aspects of human lipoprotein metabolism.