Regulation of reverse cholesterol transport - a comprehensive appraisal of available animal studies

Plasma levels of high density lipoprotein (HDL) cholesterol are strongly inversely correlated to the risk of atherosclerotic cardiovascular disease. A major recognized functional property of HDL particles is to elicit cholesterol efflux and consequently mediate reverse cholesterol transport (RCT). The recent introduction of a surrogate method aiming at determining specifically RCT from the macrophage compartment has facilitated research on the different components and pathways relevant for RCT. The current review provides a comprehensive overview of studies carried out on macrophage-specific RCT including a quick reference guide of available data. Knowledge and insights gained on the regulation of the RCT pathway are summarized. A discussion of methodological issues as well as of the respective relevance of specific pathways for RCT is also included

Cholesterol Efflux Capacity Associates with the Ankle-Brachial Index but Not All-Cause Mortality in Patients with Peripheral Artery Disease

BACKGROUND: Cholesterol efflux is an important mechanism by which high-density lipoproteins (HDLs) protect against cardiovascular disease. As peripheral artery disease (PAD) is associated with high mortality rates, mainly due to cardiovascular causes, we investigated whether cholesterol efflux capacity (CEC) of apolipoprotein B (apoB)-depleted plasma, a widely used surrogate of HDL function, may serve as a predictive marker for mortality in this patient population. METHODS: In this prospective single-center study (median follow-up time: 9.3 years), apoB-containing lipoproteins were precipitated from plasma of 95 patients with PAD and incubated with J744-macrophages, which were loaded with radiolabeled cholesterol. CEC was defined as the fractional radiolabel released during 4 h of incubation. RESULTS: Baseline CEC was lower in PAD patients that currently smoked (p = 0.015) and had a history of myocardial infarction (p = 0.011). Moreover, CEC showed a significant correlation with HDL-cholesterol (p = 0.003) and apolipoprotein A-I levels (p = 0.001) as well as the ankle-brachial index (ABI, p = 0.018). However, CEC did not differ between survivors and non-survivors. Neither revealed Kaplan-Meier and Cox regression analyses any significant association of CEC with all-cause mortality rates. CONCLUSION: Taken together, CEC is associated with ABI but does not predict all-cause mortality in patients with PAD

Group IIA Secretory Phospholipase A(2) Predicts Graft Failure and Mortality in Renal Transplant Recipients by Mediating Decreased Kidney Function

The acute phase protein group IIA secretory phospholipase A(2) (sPLA(2)-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA(2)-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA(2)-IIA was determined by ELISA. Primary end points were death-censored graft failure and mortality (median follow-up, 7.0 years). Baseline sPLA(2)-IIA was higher in RTRs than in healthy controls (median 384 ng/dL (range 86-6951) vs. 185 ng/dL (range 104-271), p <0.001). Kaplan-Meier analysis demonstrated increased risk for graft failure (p = 0.002), as well as cardiovascular (p <0.001) and all-cause mortality (p <0.001), with increasing sPLA(2)-IIA quartiles. Cox regression showed strong associations of sPLA(2)-IIA with increased risks of graft failure (hazard ratio (HR) = 1.42 (1.11-1.83), p = 0.006), as well as cardiovascular (HR = 1.48 (1.18 1.85), p = 0.001) and all-cause mortality (HR = 1.39 (1.17 1.64), p <0.001), dependent on parameters of kidney function. Renal function during follow-up declined faster in RTRs with higher baseline sPLA(2)-IIA levels. In RTRs, sPLA(2)-IIA is a significant predictive biomarker for chronic graft failure, as well as overall and cardiovascular disease mortality dependent on kidney function. This dependency is conceivably explained by sPLA(2)-IIA impacting negatively on kidney function

Impaired HDL cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status:the CODAM study

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) increase atherosclerotic cardiovascular disease risk. Cholesterol efflux capacity (CEC) is a key metric of the anti-atherosclerotic functionality of high-density lipoproteins (HDL). The present study aimed to delineate if T2DM and MetS cross-sectionally associate with altered CEC in a large high cardiometabolic risk population. CEC was determined from THP-1 macrophage foam cells towards apolipoprotein B-depleted plasma from 552 subjects of the CODAM cohort (288 controls, 126 impaired glucose metabolism [IGM], 138 T2DM). MetS was present in 297 participants. CEC was not different between different glucose tolerance categories but was lower in MetS (P <0.001), at least partly attributable to lower HDL cholesterol (HDL-C) and apoA-I levels (P <0.001 for each). Low grade inflammation was increased in IGM, T2DM and MetS as determined by a score comprising 8 different biomarkers (P <0.05-<0.001; n = 547). CEC inversely associated with low-grade inflammation taking account of HDL-C or apoA-I in MetS (P <0.02), but not in subjects without MetS (interaction: P = 0.015). This study demonstrates that IGM and T2DM do not impact the HDL CEC function, while efflux is lower in MetS, partly dependent on plasma HDL-C levels. Enhanced low-grade inflammation in MetS may conceivably impair CEC even independent of HDL-C and apoA-I

Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease

Understanding HDL function:studies in preclinical models and patients

HDL-functie draagt mogelijk bij aan het risico op hart- en vaatziekten Slecht werkende High-density lipoproteïne (HDL) draagt mogelijk bij aan het risico op hart- en vaatziekten. Dat concludeert Wijtske Annema, die onderzoek deed naar de relatie tussen HDL-functie en hart- en vaatziekten. HDL wordt over het algemeen gezien als het goede cholesterol in het lichaam. Des te hoger de hoeveelheid HDL in het bloed, des te lager het risico op hart- en vaatziekten. Recent onderzoek laat zien dat niet alleen de hoeveelheid HDL belangrijk is, maar ook de functie van het HDL. In een gecompliceerd proces, genaamd Reverse Cholesterol Transport (RCT), helpt HDL om cholesterol uit de weefsels via het plasma naar de lever te sturen, waarna het via de ontlasting het lichaam kan verlaten. Dit proces werkt mogelijk niet goed bij mensen met hart- en vaatziekten. Er is evenwel nog veel onduidelijk over de rol die HDL-functie precies speelt in hart- en vaatziekten. Annema ontdekte onder andere dat het proces van RCT minder goed werkt in het geval van een acute ontstekingsreactie en type-1 diabetes. Ook vond ze dat het HDL van mensen met een hartinfarct minder goed functioneert. Niettemin bleek HDL-functie niet het risico op toekomstige sterfte door hart- en vaatziekten te kunnen voorspellen. De promovenda concludeert dat HDL-functie meer informatie kan geven dan cholesterolwaardes, maar dat er grootschaliger bevolkingsonderzoek nodig is naar het verband tussen HDL-functie en ziekte.