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

Abstract

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.

The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease

“…One major reason for the discrepancy observed in humans and mice could be differences in the composition of lipid associated proteins. A study from Gordon et al (2015) utilized a mass spectrometry approach to demonstrate a high degree of shared homology amongst a range of proteins associated with LDL and HDL. However, a small minority of proteins did exhibit significant differences which could reflect in major metabolic differences between species (Gordon et al, 2015).…”

Impact of genetic deletion of platform apolipoproteins on the size distribution of the murine lipoproteome

“…In our previous characterization of the mouse lipoproteome [30], we identified 113 lipid-associated proteins in the WT C57Bl6 mice. We detected 114, 104 and 103 proteins in the apoA-I KO, apoA-IV KO, and apoA-II KO groups (summing WT controls and knockouts (KO)), respectively (n = 6 per group).…”

“…Mass spectrometer files (*.wiff) and corresponding Mascot DAT files were imported into Skyline. Using a spectral library cut-off score of 95%, fixed modification of Cys with carbamidomethylation and variable modification of Met by oxidation, we created a spectral library with the 113 proteins previously identified in WT C57BL6 mice [30] (max 2 missed trypsin cleavages). Skyline is designed for analyzing multiple replicates of similarly prepared samples as a hypothesis testing tool.…”

“…Conversely, proteins that do not depend on apoA-I should not be affected in its absence. Having recently demonstrated that the lipoproteome of both LDL and HDL-sized lipoproteins in the mouse exhibit a similar overall complexity to humans [23], we took advantage of the mouse model to test this hypothesis. We tracked the size distribution and relative protein levels of the plasma lipoprotein proteome in mice lacking each of the three most abundant HDL proteins, apoA-I, apoA-II and apoA-IV, and compared them to WT controls.…”

Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice

“…Not only do subclasses of HDL with different sizes co-exist in the plasma, but analysis of the proteins on HDL shows that the lipoprotein contains many proteins, exhibiting different functional attributes associated with cholesterol homeostasis, immune function, proteolysis, complement and anti-oxidation [2, 3]. Many of these proteins are present in sub-stoichiometric amounts, indicating that these proteins do not all necessarily inhabit the same particle.…”