Streptozotocin-induced diabetes in human apolipoprotein B transgenic mice: effects on lipoproteins and atherosclerosis

The effects of diabetes and lipoprotein lipase (LpL) on plasma lipids were studied in mice expressing hu- man apolipoprotein B (HuBTg). Our overall objective was to produce a diabetic mouse model in which the sole effects of blood glucose elevation on atherosclerosis could be as- sessed. Mice were made diabetic by intraperitoneal injec- tion of streptozotocin, which led to a 2- to 2.5-fold increase in plasma glucose. Lipids were assessed in mice on chow and on an atherogenic Western type diet (WTD), consisting of 21% (wt/wt) fat and 0.15% (wt/wt) cholesterol. Plasma tri- glyceride and cholesterol were the same in diabetic and non- diabetic mice on the chow diet. On the WTD, male diabetic HuBTg mice had a . 50% increase in plasma cholesterol and more very low density lipoprotein (VLDL) cholesterol and triglyceride as assessed by FPLC analysis. A Triton study showed no increase in triglyceride or apolipoprotein B pro- duction, suggesting that the accumulation of VLDL was due to a decrease in lipoprotein clearance. Surprisingly, the VLDL increase in these mice was not due to a decrease in LpL activity in postheparin plasma. To test whether LpL overexpression would alter these diabetes-induced lipopro- tein changes, HuBTg mice were crossed with mice express- ing human LpL in muscle. LpL overexpression reduced plasma triglyceride, but not cholesterol, in male mice on WTD. Aortic root atherosclerosis assessed in 32-week-old mice on the WTD was not greater in diabetic mice. In sum- mary, diabetes primarily increased plasma VLDL in HuBTg mice. LpL activity was not decreased in these animals. How- ever, additional LpL expression eliminated the diabetic lipoprotein changes. These mice did not have more athero- sclerosis with diabetes. —Kako, Y., L-S. Huang, J. Yang, T. Katopodis, R. Ramakrishnan, and I. J. Goldberg. Streptozo- tocin-induced diabetes in human apolipoprotein B trans- genic mice: effects on lipoproteins and atherosclerosis. J. Lipid Res. 1999. 40: 2185-2194.