Abstract 15489: Postprandial Elevation of Granulocyte Inflammation Associated with Delayed Triglyceride-Rich Lipoprotein Clearance Contributes to Elevated Metabolic Risk in Apolipoprotein E2 Gene Replacement Mice
Although the ε2 allele of the human APOE gene encoding apoE2 is typically associated with normal or reduced plasma lipid levels, prolonged postprandial hyperlipidemia is typical in ε2 carriers. Subjects with the ε2 allele are prone to develop Type III hyperlipoproteinemia and are at a greater risk for obesity, diabetes, and peripheral vascular disease. However, the underlying mechanism between apoE2-lipoprotein metabolism and increased metabolic disease risk is poorly understood. To better assess this relationship, we tested the hypothesis of elevated inflammation in APOE2 and APOE3 gene-replacement mice fed chow and Western-type high fat/cholesterol diet for 8 weeks. This study showed postprandial hyperlipidemia in chow-fed APOE2 mice was accompanied by increased plasma granulocyte number (p<0.001) and inflammation (characterized by iNOS+ cells) (p<0.001) 2 hr after feeding a lipid-rich meal when compared to APOE3 mice. APOE2 mice fed Western-type diet also had elevated number of granulocytes (p<0.001) and iNOS+ cells (p<0.001) when compared to APOE3 mice. Furthermore, an increase in inflammatory granulocytes and iNOS+ cells was also observed under fasting conditions in either chow or Western-fed APOE2 mice when compared to similarly fed APOE3 mice, suggesting a chronic inflammatory state regardless of diet. Additionally, Western diet-fed APOE2 mice displayed elevated levels of MCP-1 (2.4x), MIP-1α (5.5x), TNF-α (3.1x), and IL-18 (2.1x) mRNA in adipose tissues accompanied by increased adiposity when compared to similarly-fed APOE3 mice. Measurements of fasting plasma glucose and insulin levels revealed that Western diet-fed APOE2 mice were more insulin resistant than similarly-fed APOE3 mice. Taken together, these data showed that delayed postprandial triglyceride-rich lipoprotein clearance associated with apoE2 promotes postprandial inflammation, and the more robust and sustained inflammation observed in ε2 carriers under high fat/cholesterol dietary conditions contributes to adipose tissue inflammation that ultimately leads to increased adiposity and insulin resistance with corresponding increase risk of peripheral vascular disease.
- © 2011 by American Heart Association, Inc.