Abstract
To study the role of low levels of high density lipoprotein (HDL) and apolipoprotein (apo) A-I in atherosclerosis risk, human apoB transgenic mice (HuBTg) were crossed with apoA-I-deficient (apoA-I–/–) mice. After a high fat challenge, total cholesterol levels increased drastically due to an increase in the non-HDL cholesterol as confirmed by FPLC analysis. In addition, total cholesterol levels in A-I–/– HuBTg mice were lower than the control HuBTg mice, due mainly to decreased HDL-C in A-I–/– HuBTg mice. Analysis of atherosclerosis in the proximal aorta in mice fed a high-fat Western-type diet for 27 weeks revealed a 200% greater lesion area in female apoA-I–/– HuBTg mice (49740 ± 9751 μm2) compared to control HuBTg mice (23320 ± 4981 μm2, P = 0.03). Lesion size (12380 ± 3281 μm2) in male A-I–/– HuBTg mice was also about 200% greater than that in the control HuBTg mice (5849 ± 1543 μm2), although not statistically significant. Very few and small lesions were observed in both apoA-I–/– HuBTg and control HuBTg animals fed a chow diet. Therefore, the adverse effect of low HDL on atherosclerosis in mice was only evident when LDL-cholesterol was markedly elevated by high-fat challenge. Male apoA-I–/– HuBTg mice exhibited hypertriglyceridemia when challenged with a high-fat diet. This correlated with both a reduction in lipoprotein lipase activity and a decrease in lipoprotein lipase activation by HDL. In summary, low high density lipoprotein levels due to apolipoprotein A-I deficiency exacerbated the development of atherosclerotic lesions in mice with elevated atherogenic lipoproteins. This mouse model mimics human conditions associated with low HDL levels and provides additional evidence for the anti-atherogenic role of apoA-I.—Voyiaziakis, E., I. J. Goldberg, A. S. Plump, E. M. Rubin, J. L. Breslow, and L-S. Huang. ApoA-I deficiency causes both hypertriglyceridemia and increased atherosclerosis in human apoB transgenic mice.
Highlights
To study the role of low levels of high density lipoprotein (HDL) and apolipoprotein A-I in atherosclerosis risk, human apoB transgenic mice (HuBTg) were crossed with Apolipoprotein A-I (apoA-I)-deficient mice
Female mice developed much more extensive lesions; approximately 4-fold greater lesion area was found between comparable genotypes. These results demonstrated that low HDL levels due to apoA-I deficiency exacerbated the development of atherosclerotic lesions in mice containing elevated low density lipoprotein (LDL) levels due to overexpression of the human apoB transgene
We demonstrated that low HDL levels due to apoA-I deficiency exacerbated the development of atherosclerotic lesions in mice with elevated LDL levels, a mouse model generated by crossing the apoA-Ideficient and human apoB transgenic mouse lines
Summary
ApoA-I-deficient mice (apoA-IϪ/Ϫ) were created by gene targeting techniques in ES cells as described [16, 17]. HuBTg and wild types littermates from the previous cross were intercrossed to generate HuBTg mice for experiments. Age-matched (14–16 week old) male apoA-IϪ/Ϫ HuBTg and HuBTg mice were fed WTD for 4 weeks (first set) or 8 weeks (second set). LPL and hepatic triglyceride lipase (HTGL) assays were performed using PHP from age-matched mice (14–16 weeks old) fed either chow or WTD for 2 weeks prior to assay. Plasma samples were collected from fasted mice fed WTD for 23 weeks since the age of 4 weeks. Plasma samples were incubated at 56ЊC for 1 h prior to assay to inactivate HTGL activity found in mouse pre-heparin plasma. A standard source of LPL purified as described previously [28] was added, and the assay was allowed to proceed for 60 min at 27ЊC. All assays were performed in triplicate and the data for the hydrolysis of TG, i.e., LPL activity, were compared
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