High-Density Lipoprotein Proteomic Composition, and not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets

Abstract

H igh-density lipoprotein (HDL) particles play a pivotal role in reverse cholesterol transport (RCT) by facilitating cholesterol efflux from peripheral cells and delivering acquired lipid to the liver for elimination in the feces. 1 Obesity increases the risk of developing cardiovascular disease (CVD) 2 ; however, little is known about the impact of obesity on HDL function and RCT. Chronic inflammation is a classic hallmark of obesity 3 and CVD, 4 and it is plausible there is a common inflammatory-driven mechanism Background-Acute inflammation impairs reverse cholesterol transport (RCT) and reduces high-density lipoprotein (HDL) function in vivo. This study hypothesized that obesity-induced inflammation impedes RCT and alters HDL composition, and investigated if dietary replacement of saturated (SFA) for monounsaturated (MUFA) fatty acids modulates RCT. Methods and Results-Macrophage-to-feces RCT, HDL efflux capacity, and HDL proteomic profiling was determined in C57BL/6j mice following 24 weeks on SFA-or MUFA-enriched high-fat diets (HFDs) or low-fat diet. The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma 3 H-cholesterol counts during RCT in vivo and ATP-binding cassette, subfamily A, member 1-independent efflux to plasma ex vivo, effects that were attributable to elevated HDL cholesterol. By contrast, ATP-binding cassette, subfamily A, member 1-dependent efflux was reduced after both HFDs, an effect that was also observed with insulin resistance and high SFA consumption in humans. SFA-HFD impaired liver-to-feces RCT, increased hepatic inflammation, and reduced ABC subfamily G member 5/8 and ABC subfamily B member 11 transporter expression in comparison with low-fat diet, whereas liver-to-feces RCT was preserved after MUFA-HFD. HDL particles were enriched with acute-phase proteins (serum amyloid A, haptoglobin, and hemopexin) and depleted of paraoxonase-1 after SFA-HFD in comparison with MUFA-HFD. Conclusions-Ex vivo efflux assays validated increased macrophage-to-plasma RCT in vivo after both HFDs but failed to capture differential modulation of hepatic cholesterol trafficking. By contrast, proteomics revealed the association of hepatic-derived inflammatory proteins on HDL after SFA-HFD in comparison with MUFA-HFD, which reflected differential hepatic cholesterol trafficking between groups. Acute-phase protein levels on HDL may serve as novel biomarkers of impaired liver-to-feces RCT in vivo. Correspondence to Fiona C. McGillicuddy, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland. E-mail fiona.mcgillicuddy@ucd.ie © 2016 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial pur...

Can We Make High-Density Lipoproteins Great Again?

“…11 HDL subfractions from human subjects with acute coronary syndrome have a high inflammatory index and high lipid hydroperoxide levels, which are accompanied with significantly lower levels of PON1 and cholesterol efflux ability. 12 In line with the observations of O'Reilly et al, 5 diets supplemented with olive oil have been shown in a mouse model to increase PON1 activity and the cholesterol efflux ability of HDL. 13 Moreover, in a small study with 8 human male subjects, a Mediterranean diet was also shown to increase plasma carotenoids and PON1 activity, as well as a decrease of C-reactive protein.…”

“…Interestingly, although there was an increase in plasma concentrations of small HDL particles in SFA-fed mice, the small HDL particles from these mice had an impaired ability to efflux cholesterol from macrophages via the transporter ATP-binding cassette A1. In support of their animal studies showing that a high-fat diet enriched with SFAs negatively influences HDL functionality, O'Reilly et al 5 also showed that the HDL from human subjects receiving >10% of calories from SFAs had an impaired ability to efflux cholesterol from macrophages via ATP-binding cassette A1. They also showed that the HDL from human subjects with insulin resistance had an impaired ATP-binding cassette A1-mediated cholesterol efflux ability.…”

“…In this issue of Circulation, O'Reilly et al 5 examined how HDL function changes in response to high-fat diets enriched with saturated fatty acids (SFAs) or monounsaturated fatty acids (MUFAs). Using a mouse model that received 45% of calories from either SFA or MUFA over a 24-week period, the authors found that, in comparison with mice fed the MUFAenriched diet, mice fed the SFA-enriched diet exhibited impaired macrophage-to-feces RCT.…”

“…Using a proteomics approach, O'Reilly et al 5 showed that the protein content of small HDL particles differed between mice fed the high-fat diet enriched with SFAs versus the mice fed the high-fat diet enriched with MUFAs. Of note, the authors identified an increase in the amount of the acutephase inflammatory protein serum amyloid A (SAA) 1 and SAA2 that were associated with the small HDL particles from SFA-fed mice versus MUFA-fed mice.…”

“…In addition, O'Reilly et al 5 showed an increase in the amount of paraoxonase 1 (PON1) that was associated with the small HDL particles from MUFA-fed mice versus SFA-fed mice. PON1, together with glutathione peroxidase, can prevent the oxidation of HDL phospholipids.…”