HDL biology
LDL receptor enables a CETP-independent route for macrophage cholesterol to reach faeces, mouse study finds (Circ Res 2020)
Original title: LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis: Insight From Mouse Models
Researchers investigated whether LDL particles can act as an intermediate reservoir for macrophage-derived unesterified cholesterol on its way to faecal excretion, using mouse models of hypercholesterolemia that are naturally deficient in CETP. LDL induced efflux of radiolabelled unesterified cholesterol from cultured macrophages, and this cholesterol transferred rapidly from HDL to LDL when both were present. Macrophage-to-faeces reverse cholesterol transport rates were significantly reduced in LDL receptor knockout mice, LDL receptor knockout mice expressing human APOB100, and PCSK9-overexpressing mice, but unchanged in APOB100-transgenic mice with intact LDL receptor. The findings establish that, alongside the classic HDL-dependent pathway to the liver, a distinct CETP-independent route exists in which the LDL receptor moves macrophage cholesterol to the liver for excretion.
Original abstract
Rationale: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. 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 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 was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) 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 cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B-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 (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.