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Published on: September 26, 2018
Apo E structure determines VLDL clearance and atherosclerosis risk in mice
C Knouff1, M E Hinsdale, H Mezdour
1Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7525, USA.
Abstract:
We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.
Insights
Mice expressing human apo E4 (apolipoprotein E4) showed significantly higher cholesterol and VLDL levels compared to apo E3 mice. This suggests apo E4 structure directly impacts VLDL clearance and atherosclerosis risk.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Science
Background:
- Apolipoprotein E (apo E) is crucial for lipid metabolism.
- Different apo E isoforms (E2, E3, E4) are associated with varying cardiovascular disease risks.
- Understanding isoform-specific effects on lipid transport and atherosclerosis is vital.
Purpose of the Study:
- To investigate the functional consequences of the human apo E4 isoform compared to the apo E3 isoform in mice.
- To determine the impact of apo E isoform structure on very-low-density lipoprotein (VLDL) metabolism and atherosclerosis development.
Main Methods:
- Generated transgenic mice expressing human apo E4 (4/4) or apo E3 (3/3) in place of endogenous apo E.
- Analyzed plasma lipid and apolipoprotein levels on various diets.
- Assessed VLDL composition, VLDL receptor binding, and VLDL clearance rates.
- Quantified atherosclerotic plaque size in response to an atherogenic diet.
Main Results:
- No significant differences in plasma lipids between 4/4 and 3/3 mice on chow diet.
- 4/4 mice exhibited approximately double the cholesterol, apo E, and apo B-48 in their VLDL compared to 3/3 mice across all diets.
- 4/4 VLDL showed slightly enhanced binding to the LDL receptor but had a 50% reduced clearance rate compared to 3/3 VLDL.
- A trend towards larger atherosclerotic plaque size was observed in 4/4 mice on an atherogenic diet.
Conclusions:
- Structural differences in apo E protein isoforms are sufficient to alter VLDL residence time.
- Impaired VLDL clearance in apo E4 mice is linked to increased atherosclerosis risk.
- These findings highlight the direct role of apo E isoform structure in modulating lipoprotein metabolism and cardiovascular disease susceptibility.
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