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 [3H]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 [3H]cholesterol efflux to plasma and HDL-derived [3H]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.