-Acute inflammation impairs Reverse Cholesterol Transport (RCT) and reduces high-density lipoprotein (HDL) functionin 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. -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(3)H-cholesterol counts during RCTin vivoand ABCA1-independent efflux to plasmaex 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. -Ex vivoefflux assays validated increased macrophage-to-plasma RCTin vivoafter 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 RCTin vivo.
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