Joan Carles Escolà-Gil, Spain
Institut d’Investigacions Biomèdiques (IIB) Sant Pau Biochemistry
Presenter of 2 Presentations
Live Q&A
Session Time
13:00 - 14:00
Lecture Time
13:30 - 14:00
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LDL receptor regulates the reverse transport of macrophage-derived unesterified cholesterol via concerted action of the HDL-LDL axis
Session Time
13:00 - 14:00
Lecture Time
13:15 - 13:20
Background and Aims
HDL-mediated stimulation of cholesterol efflux from macrophage foam cells initiates the reverse cholesterol pathway (m-RCT) which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). We investigated the role of LDL as an intermediate UC carrier in m-RCT.
Methods
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 (FH) was assessed. In vivo m-RCT was evaluated in CETP lacking mouse models of hypercholesterolemia fed a Western-type diet.
Results
LDL facilitated the removal 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 the CEC of HDL or of FH plasma. The m-RCT rates of radiolabeled UC for LDL receptor (LDLr)-KO, LDLr-KO/apoB-100, and PCSK9-overexpressing mice were all significantly attenuated compared with those of wild-type mice. In contrast, the m-RCT rate remained unchanged in apoB-100 overexpressing transgenic mice with fully functional LDLr, despite increased levels of plasma apoB-containing lipoproteins.
Conclusions
We conclude that hepatic LDLr contributes to the flow of macrophage-derived UC to feces in mice, while hyper-apoB lipoproteinemia per se is unable to further stimulate the m-RCT. The results suggest that, besides the major HDL-dependent m-RCT pathway via SR-BI to the liver, a CETP-independent m-RCT path exists in mice in which LDL mediates the transfer of UC cholesterol from macrophages to feces.
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