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.

BackgroundThe pathophysiology of cardiovascular complications in people with type 1 diabetes (T1DM) remains unclear. An increase in epicardial adipose tissue (EAT) and alterations in the composition of high-density lipoprotein (HDL) are associated with coronary artery disease, but information on its relationship in T1DM is very limited. Our aim was to determine the association between EAT volume, subclinical atherosclerosis, and HDL composition in type 1 diabetes.MethodsSeventy-two long-term patients with T1DM without clinical atherosclerosis were analyzed. EAT volume and subclinical atherosclerosis were measured using cardiac computed tomography angiography. EAT was adjusted according to body surface to obtain an EAT index (iEAT). HDL composition was determined.ResultsThe mean iEAT was 40.47 ± 22.18 cc/m2. The bivariate analysis showed positive associations of the iEAT with gender, age, hypertension, dyslipidemia, smoking, body mass index, waist circumference, insulin dose, and triglyceride (P < 0.05). The iEAT correlated positively with small HDL, increased content of apolipoprotein (apo)A-II and apoC-III, and decreased content of apoE and free cholesterol. Multiple linear regression showed that age, apoA-II content in HDL, and waist circumference were independently associated with the iEAT. Fifty percent of the patients presented subclinical atherosclerotic lesions. These patients had a higher iEAT, and their HDL contained less cholesterol and more apoA-II and lipoprotein-associated phospholipase A2 than patients without subclinical atherosclerosis.ConclusionAlterations in the composition of HDL in TIDM are associated with increased iEAT and the presence of subclinical atherosclerosis. We propose that these abnormalities of HDL composition could be useful to identify T1DM patients at highest cardiovascular risk.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0794-9) contains supplementary material, which is available to authorized users.

Please cite this article as: Dias IH, Ferreira R, Gruber F, Vitorino R, Rivas-Urbina A, Sanchez-Quesada JL, Vieira Silva J, Fardilha M, de Freitas V, Reis A, Sulfate-based lipids: analysis of healthy human fluids and cell extracts, Chemistry and Physics of Lipids (2019), https://doi.

LDL(-) induced the release of MMP-9 and TIMP-1 in monocytes through CD14. SDX affects the ability of LDL(-) to promote TIMP-1 and MMP-9 release by its interaction with LDL(-).