Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin

Abstract

Atherosclerosis is accelerated in people with systemic lupus erythematosus, and the presence of dysfunctional, pro-inflammatory high-density lipoproteins is a marker of increased risk. We developed a mouse model of multigenic lupus exposed to environmental factors known to accelerate atherosclerosis in humans - high-fat diet with or without injections of the adipokine leptin. BWF1 mice were the lupus-prone model; BALB/c were non-autoimmune controls. High-fat diet increased total serum cholesterol in both strains. In BALB/c mice, non-high-density lipoprotein cholesterol levels increased; they did not develop atherosclerosis. In contrast, BWF1 mice on high-fat diets developed increased quantities of high-density lipoproteins as well as elevated high-density lipoprotein scores, indicating pro-inflammatory high-density lipoproteins; they also developed atherosclerosis. In the lupus-prone strain, addition of leptin increased pro-inflammatory high-density lipoprotein scores and atherosclerosis, and accelerated proteinuria. These data suggest that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background.

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: Total cholesterol levels increased significantly in both BALB/c and BWF1 mice on high-fat diets. BWF1 mice on high-fat diet plus leptin had elevated levels similar to those in the same strain on high-fat diet alone. * = p < 0.01 compared with BALB/c on regular diet: ** p < 0.001 compared with BWF1 on regular diet, using ANOVA analysis with Tukey’s comparison of columns. Panel B: Non-HDL cholesterol levels in each group. Levels are significantly higher in BALB/c mice, on either regular or high-fat diets, compared to BWF1 mice in any group. In BWF1 mice, levels did not increase significantly on high-fat diet with or without leptin. * = p < 0.05 compared with same treatment group of BWF1 mice. Panel C: Mean ± SD for total HDL levels show similar levels in BALB/c and BWF1 mice on regular chow. Significant increases occurred in BW on high-fat diet with or without leptin, compared with BWF1 on chow. * p < 0.001. Differences between high-fat diet in BWF1 and high-fat diet plus leptin were not significant. Panel D: HDL functional scores in each group show significantly higher scores for BWF1 on high-fat or on high-fat diet plus leptin, compared with BWF1 on normal chow. Levels in BALB/c did not differ significantly between the chow and high-fat groups. * p < 0.001 for each of the treated BWF1 groups compared with each of the BALB/c groups. ** p = 0.005 comparing BWF1 high fat with high fat plus leptin, one-tailed paired t-test.

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 regular chow. However, there were significant increases in numbers of lesions in BWF1 on high-fat diets The numbers were significantly higher in BWF1 mice on high fat plus leptin. * p < 0.05 compared with BALB/c and with BWF1 on regular chow. ** p < 0.03 comparing BWF1 mice on high fat with high fat plus leptin. Data by ANOVA for all groups and by one-tailed paired t-test for comparison of leptin plus high fat with high fat in BWF1. Panel B. Effect of diets on proteinuria in BWF1 mice. Here mice were studied for 28 weeks after introduction of diets. There were 10 mice in each group. By ANOVA, proteinuria occurred significantly earlier in mice on high-fat-diet-plus-leptin than in the other groups, p < 0.05.