APOA-I DEFICIENCY CAUSES BOTH HYPERTRIGLYCERIDEMIA AND INCREASED ATHEROSCLEROSIS IN HUMAN APO-B TRANSGENIC MICE

To study the role of low levels of high density lipoprotein (HDL) and apolipoprotein (ape) A-I in atherosclerosis risk, human apoB transgeni c mice (HuBTg) were crossed with apoA-I-deficient (apoA-I-/-) mice. Af ter a high fat challenge, total cholesterol levels increased drastical ly 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 HDLC i n A-I(-/-)HuBTg mice. Analysis of atherosclerosis in the proximal aort a 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 mu m(2)) compared to control HuBTg mice (23320 +/- 4981 mu m(2), P = 0 .03). Lesion size (12380 +/- 3281 mu m(2)) in male A-I(-/-)HuBTg mice was also about 200% greater than that in the control HuBTg mice (5849 +/- 1543 mu m(2)), although not statistically significant. Very few an d small lesions were observed in both apoA-I(-/-)HuBTg and control HuB Tg animals fed a chow diet. Therefore, the adverse effect of low HDL o n atherosclerosis in mice was only evident when LDL-cholesterol was ma rkedly elevated by high-fat challenge. Male apoA-I(-/-)HuBTg mice exhi bited 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 exace rbated the development of atherosclerotic lesions in mice with elevate d atherogenic lipoproteins. This mouse model mimics human conditions a ssociated vith low HDL levels and provides additional evidence for the anti-atherogenic role of apoA-I.