Abstract
Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.
Highlights
Apolipoprotein E4 is associated with inflammatory metabolic diseases
When the mice were fed a Western-type high fat, high cholesterol diet for 4 weeks, significant body weight gain was observed only in the APOE3 mice, and the APOE4 mice did not show body weight difference after 4 weeks of feeding the hypercaloric Western-type diet (Fig. 1A). These results confirmed results reported previously, and our data showed that body fat mass was significantly lower in Western diet-fed APOE4 mice compared with APOE3 mice (Fig. 1B)
We showed that, in comparison with APOE3 macrophages, the APOE4 macrophages are dysfunctional with impaired efferocytosis of apoptotic cells
Summary
Apolipoprotein E4 (apoE4) is associated with inflammatory metabolic diseases. Results: Human APOE4 gene replacement mice displayed elevated tissue inflammation. APOE4 macrophages showed impaired efferocytosis, increased apoptosis, and endoplasmic reticulum stress. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism
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