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

Abstract

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 [ 3 H]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 [ 3 H]cholesterol efflux to plasma and HDL-derived [ 3 H]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 [ 3 H]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. ietary saturated fat intake has been associated with an increased risk of atherosclerotic cardiovascular disease and metabolic diseases, such as obesity and type 2 diabetes. 1,2 This effect is thought to be mediated by an increase in plasma cholesterol, mainly low-density lipoprotein cholesterol. 3 However, both dietary saturated fat and cholesterol intake are known to raise plasma high-density lipoprotein cholesterol (HDL-C) levels. 4 -8 Several epidemiological studies and 1 meta-analysis of 60 controlled trials showed a positive correlation between high saturated fat intake and HDL-C. 9 -11 In an attempt to determine the mechanism underlying this paradoxical observation, several studies reported that a low saturated fat and cholesterol intake reduced HDL-C levels by reducing the apolipoprotein A-I secretion rate. [12][13][14] However, other studies found this effect to be associated with decreased apolipoprotein A-I fractional catabolic rates. 15,16 Also, when dietary cholesterol was increased along with total and saturated fat, increases in large high-density lipoprotein (HDL) subpopulations and HDL apolipoprotein E amounts were observed. 7,17 Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms. 18 HDL plays a critical role in cholesterol efflux from macrophages, the first step in RCT. 18 However, despite the reported changes in HDL compositi...

Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

“…ABCG5 and ABCG8, in particular, do not appear to be regulated by estrogen52. These transporters are known LXR targets required for LXR agonist-mediated stimulation of cholesterol excretion55, the liver ABCG5/G8 heterodimer being a key determinant of the M-RCT stimulation induced by LXR agonists and a high-cholesterol diet5657. By analogy with the effect of SERMs on cultured cells (reported here and elsewhere1115), a disruption of intracellular cholesterol trafficking in hepatocytes may be involved in the reduction of ABCG5/G8 expression.…”

“…HDL (1.063–1.21 kg/L) was isolated by sequential ultracentrifugation of pooled plasma from male mice treated with a western-type diet and TAM, RAL or vehicle as described above and labeled with [1,2- 3 H(N)]cholesteryl oleate (Perkin-Elmer) as reported5657. [1,2- 3 H(N)]cholesteryl oleate-labeled HDL were injected intravenously into mice (2 × 10 6 dpm/mouse) that were being treated with the same SERM or vehicle as the HDL donor mouse (“autologous” HDL).…”

“…Liver lipids were extracted from 100 mg of liver with isopropyl alcohol-hexane 2:3 (v/v) and, after the addition of Na 2 SO 4 , the hexane phase was isolated, dried with N 2 , reconstituted with 0.5% sodium cholate and sonicated for 10 min (50 Hz) before lipid measurements. Lipids were measured by enzymatic methods using a BM/Hitachi 917 autoanalyzer as described57. Protein concentration was measured using the BCA kit (Thermo Scientific).…”

Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta

“…The HFHC diet incited a compensatory increase of HDL to promote macrophage reverse cholesterol transport and fecal excretion. 35 As a reservoir of apoprotein C-II, elevated HDL activated LPL, which hydrolyzes most of the chylomicron TG to FFA. The HFHC diet significantly increased serum TG, LPL and FFA.…”

Interleukin-32 promotes lipid accumulation through inhibition of cholesterol efflux

“…RCT is a process during which cholesterol in peripheral cells is effluxed into circulating HDL and transported back into the liver for excretion in bile and feces (7). The cholesterol efflux from cells to HDL is a rate-limiting step of RCT (8). The family of ATP-binding cassette (ABC) transporters, including ABCA1 and ABCG1, has been demonstrated to serve a critical role in the RCT pathway by promoting the translocation of cholesterol across cellular bilayer membranes (9,10).…”