Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism
and vascular inflammation.
Authors Johnson LA, Kim HS, Knudson MJ, Nipp CT, Yi X, Maeda N
Submitted By Nobuyo Maeda on 7/10/2013
Status Published
Journal Journal of lipid research
Year 2013
Date Published 2/1/2013
Volume : Pages 54 : 386 - 396
PubMed Reference 23204275
Abstract Diabetes is a major risk factor for cardiovascular disease. To examine how
diabetes interacts with a mildly compromised lipid metabolism, we introduced the
diabetogenic Ins2(C96Y/+) (Akita) mutation into mice expressing human apoE4 (E4)
combined with either an overexpressing human LDL receptor gene (hLDLR) or the
wild-type mouse gene. The hLDLR allele caused 2-fold reductions in plasma
HDL-cholesterol, plasma apoA1, and hepatic triglyceride secretion. Diabetes
increased plasma total cholesterol 1.3-fold and increased apoB48 secretion
3-fold, while reducing triglyceride secretion 2-fold. Consequently, diabetic E4
mice with hLDLR secrete increased numbers of small, cholesterol-enriched,
apoB48-containing VLDL, although they have near normal plasma cholesterol (<120
mg/dl). Small foam cell lesions were present in the aortic roots of all diabetic
E4 mice with hLDLR that we analyzed at six months of age. None were present in
nondiabetic mice or in diabetic mice without hLDLR. Aortic expression of genes
affecting leukocyte recruitment and adhesion was enhanced by diabetes. ApoA1
levels, but not diabetes, were strongly correlated with the ability of plasma to
efflux cholesterol from macrophages. We conclude that the diabetes-induced
proinflammatory changes in the vasculature and the hLDLR-mediated cholesterol
accumulation in macrophages synergistically trigger atherosclerosis in mice with
human apoE4, although neither alone is sufficient.

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina
Xianwen YiUniversity of North Carolina at Chapel Hill