LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis

Abstract

Rationale: The HDL-mediated stimulation of cellular cholesterol efflux initiates the reverse cholesterol pathway from macrophages (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity (CEC). However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. Objective: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Methods and Results: Macrophage cholesterol efflux induced either in vitro by LDL added to the culture media either alone or together with HDL, or ex vivo by plasma derived from subjects with familial hypercholesterolemia (FH), was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL CEC in the FH plasma. The m-RCT rates of the LDL receptor (LDLr)-KO, LDLr-KO/APOB100, and PCSK9-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in human APOB100 transgenic mice with fully functional LDLr, despite increased levels of plasma APOB-containing lipoproteins. Conclusions: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces.

Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

“…However, cholesterol efflux is only the first step of the overall process, and, importantly, macrophage-specific reverse cholesterol transport to feces in vivo (m-RCT) was impaired in NAM HD-treated ApoE-deficient mice [ 61 ]. Therefore, delayed plasma clearance of non-HDL might underlie defective m-RCT [ 61 ], as observed in LDL receptor knockout mice [ 69 ]. Overall, the detrimental effect of NAM HD treatment on m-RCT, in the context of a concomitantly severely worsening hyperlipidemia, highlights the antiatherogenic power of this compound at least in mice.…”

Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study

“…One mechanism could be related to oxidized LDL (34,37). Work in experimental animals interestingly suggests that lack of functional hepatic LDLRs attenuate RCT via concerted action of the HDL-LDL-axis (38). Regardless of the mechanism, findings in adolescent FH subjects support that HDL function is altered early in life (39).…”

The effect of transgender hormonal treatment on high density lipoprotein cholesterol efflux capacity

“…It has been shown that LDL can induce cholesterol efflux from cultured macrophage foam cells via the ABCA1 transporter 49 . In our experimental setting we may exclude the contribution of LDL to cholesterol efflux since CEC studies have been performed by incubating cells with the serum fraction containing only HDL.…”