High Density Lipoprotein Proteomic Composition, and Not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets
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) fat 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 (HFD) or low-fat diet (LFD). The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma 3H-cholesterol counts during RCT in vivo and ABCA1-independent efflux to plasma ex vivo, effects which were attributable to elevated HDL-cholesterol (C). By contrast ABCA1-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 ABCG5/8 and ABCB11 transporter expression compared to LFD, while 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 compared to 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 association of hepatic-derived inflammatory proteins on HDL after SFA-HFD compared to 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.
- HDL function
- reverse cholesterol transport
- high-density lipoprotein cholesterol
- fatty acid
- Received November 6, 2015.
- Revision received February 24, 2016.
- Accepted March 18, 2016.
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 (http://creative commons.org/licenses/by-nc/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.