The Cholesterol Content of Western Diets Plays a Major Role in the Paradoxical Increase in High-Density Lipoprotein Cholesterol and Upregulates the Macrophage Reverse Cholesterol Transport Pathway

Objective-A high-saturated fatty acid-and cholesterol-containing (HFHC) diet is considered to be a major risk factor for cardiovascular disease. The present study aimed to determine the effects of this Western-type diet on high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT) from macrophages to feces. Methods and Results-Experiments were carried out in mice fed a low-fat, low-cholesterol diet, an HFHC diet, or an HFHC diet without added cholesterol (high-saturated fatty acid and low-cholesterol [HFLC]). The HFHC diet caused a significant increase in plasma cholesterol, HDL cholesterol, and liver cholesterol and enhanced macrophage-derived [H-3] cholesterol flux to feces by 3- to 4-fold. These effects were greatly reduced in mice fed the HFLC diet. This HFHC diet-mediated induction of RCT was sex independent and was not associated with obesity or insulin resistance. The HFHC diet caused 1.4- and 3-fold increases in [H-3] cholesterol efflux to plasma and HDL-derived [H-3] tracer fecal excretion, respectively. Unlike a low-fat, low-cholesterol and HFLC diets, the HFHC diet increased liver ABCG5/G8 expression. The effect of the HFHC diet on fecal macrophage-derived [3H] cholesterol excretion was totally blunted in ABCG5/G8-deficient mice. Conclusion-Despite its deleterious effects on atherosclerosis, the HFHC diet promoted a sustained compensatory macrophage-to-feces RCT. Our data provide direct evidence of the crucial role of dietary cholesterol signaling through liver ABCG5/G8 upregulation in the HFHC diet-mediated induction of macrophage-specific RCT. (Arterioscler Thromb Vasc Biol. 2011;31:2493-2499.)