As shown in , BWF1 and BALB/c mice on high-fat diets developed significant elevations in plasma levels of total cholesterol (panel A). In both strains, hypercholesterolemia appeared after 5 weeks of high-fat diet and persisted throughout the study (data not shown).
Figure 1 Plasma levels of lipids in BALB/c and BWF1 mice treated with regular or high-fat diet, and in BWF1 mice who in addition to high-fat diets received leptin injections. Each group contains 8–11 mice. Data are shown as mean ± SD. Panel A: (more ...)
The content of the hypercholesterolemia induced by high-fat diets was quite different in the two strains. Non-HDL cholesterol (containing LDL and very low-density lipoproteins (VLDL)) was significantly higher in BALB/c mice than in BWF1 (panel B), and was not influenced by high-fat diet. In contrast, (Panel C), total quantitative HDL was similar in BALB/c and BWF1 on regular chow, but addition of high-fat diet significantly increased total HDL cholesterol in the BWF1 in both high-fat diet and high-fat-diet-plus-leptin groups. As shown in Panel D, qualitative analysis of HDL showed that exposure to high-fat diet induced dysfunctional HDL in the lupus-prone strain, but not in the controls. BWF1 mice on high-fat diets had significant elevations in their functional HDL scores, indicating the presence of piHDL. Addition of leptin to the high-fat diet further increased the piHDL score in BWF1 mice. Therefore, hypercholesterolemia induced by high-fat diet consists primarily of HDL in BWF1 mice, but not in BALB/c, and the quantitatively increased HDL in BWF1 is qualitatively abnormal. BALB/c HDL are not subject to these changes.
Plasma levels of triglycerides were significantly increased by leptin plus high-fat diet but not by high-fat diet alone in BWF1 mice (data not shown).
At the histological level, the numbers of aortic lipid-containing lesions, i.e. early atherosclerotic lesions, were altered by both high-fat diet and high-fat diet plus leptin in the BWF1 mice, but not in the BALB/c controls (, panel A). The numbers of lesions paralleled the increase in piHDL (, panel D). Leptin added to high-fat diet produced significantly more lesions in BWF1 than the diet alone (, panel A).
Figure 2 Effects of treatments on disease expression. Panel A shows mean ± SD of lipid-staining aortic lesions per µM2 for each group (four mice per group). There were few lesions in BALB/c mice on regular or high-fat diets, or in BWF1 mice on (more ...)
Finally, as shown in panel B, the addition of leptin to high-fat diet resulted in acceleration of nephritis in BWF1 mice. For these studies mice were followed for a total of 28 weeks, at which time unmanipulated mice have anti-DNA and a few (<10%) develop proteinuria. The differences in proteinuria were not associated with any differences in serum levels of anti-DNA (data not shown).