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Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease.

Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.

BackgroundThe etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities.MethodsWe measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively.ResultsWe found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (−16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA.ConclusionsWe demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition.

Air particulate matter (PM) exposure has been associated with increased cardiovascular risk, especially in obesity. By triggering inflammation and oxidative stress, PM could impact atheroprotection by high-density lipoproteins (HDL). The aim of the study was to assess the relationship between short-term exposure to PM and HDL function, and the modifying effect of body mass index (BMI). Daily exposures to PM10 and PM2.5 of 50 subjects with overweight/obesity and 41 healthy volunteers with BMI < 30 kg/m2 were obtained from fixed monitoring stations. HDL function was assessed as promotion of nitric oxide (NO) release by endothelial cells and reduction in cholesterol in macrophages. HDL-induced NO release progressively declined with the increase in BMI. No association was found between HDL function and PM exposure, but a modifying effect of BMI was observed. The positive association between PM10 exposure at day −1 and NO production found at normal BMI values was lost in participants with higher BMI. Similar results were obtained for the reduction in macrophage cholesterol. The loss of the compensatory response of HDL function to PM exposure at increasing BMI levels could contribute to the endothelial dysfunction induced by PM and help to explain the susceptibility of subjects with obesity to air pollution.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells.

Low high-density lipoprotein-cholesterol (HDL-c) is the most remarkable lipid trait both in mild-to-moderate chronic kidney disease (CKD) patients as well as in advanced renal disease stages, and we have previously shown that reduced lecithin:cholesterol acyltransferase (LCAT) concentration is a major determinant of the low HDL phenotype. In the present study, we test the hypothesis that reduced LCAT concentration in CKD contributes to the progression of renal damage. The study includes two cohorts of subjects selected from the PLIC study: a cohort of 164 patients with CKD (NefroPLIC cohort) and a cohort of 164 subjects selected from the PLIC participants with a basal estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 (PLIC cohort). When the NefroPLIC patients were categorized according to the LCAT concentration, patients in the 1st tertile showed the highest event rate at follow-up with an event hazard ratio significantly higher compared to the 3rd LCAT tertile. Moreover, in the PLIC cohort, subjects in the 1st LCAT tertile showed a significantly faster impairment of kidney function compared to subjects in the 3rd LCAT tertile. Serum from subjects in the 1st LCAT tertile promoted a higher reactive oxygen species (ROS) production in renal cells compared to serum from subjects in the third LCAT tertile, and this effect was contrasted by pre-incubation with recombinant human LCAT (rhLCAT). The present study shows that reduced plasma LCAT concentration predicts CKD progression over time in patients with renal dysfunction, and, even more striking, it predicts the impairment of kidney function in the general population.

Mutations in the CETP gene resulting in defective CETP activity have been shown to cause remarkable elevations of plasma HDL-C levels, with the accumulation in plasma of large, buoyant HDL particles enriched in apolipoprotein E. Genetic CETP deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions. Aim of the present study was to assess the ability of HDL obtained from CETP-deficient subjects to protect endothelial cells from the development of endothelial dysfunction. HDL isolated from one homozygous and seven heterozygous carriers of CETP null mutations were evaluated for their ability to down-regulate cytokine-induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells. When compared at the same protein concentration, HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down-regulating cytokine-induced VCAM-1, while carrier HDL2 were more effective than control HDL2 in inhibiting VCAM-1 expression. On the other hand, HDL and HDL fractions from carriers of CETP deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production, due to a reduced eNOS activating capacity, likely because of a reduced S1P content. In conclusion, the present findings support the notion that genetic CETP deficiency, by affecting HDL particle structure, impacts on HDL vasculoprotective functions. Understanding of these effects might be important for predicting the outcomes of pharmacological CETP inhibition.

ACAT2 is the exclusive cholesterol-esterifying enzyme in hepatocytes and enterocytes. Hepatic ABCA1 transfers unesterified cholesterol (UC) to apoAI, thus generating HDL. By changing the hepatic UC pool available for ABCA1, ACAT2 may affect HDL metabolism. The aim of this study was to reveal whether hepatic ACAT2 influences HDL metabolism. WT and LXRα/β double knockout (DOKO) mice were fed a western-type diet for 8 weeks. Animals were i.p. injected with an antisense oligonucleotide targeted to hepatic ACAT2 (ASO6), or with an ASO control. Injections started 4 weeks after, or concomitantly with, the beginning of the diet. ASO6 reduced liver cholesteryl esters, while not inducing UC accumulation. ASO6 increased hepatic ABCA1 protein independently of the diet conditions. ASO6 affected HDL lipids (increased UC) only in DOKO, while it increased apoE-containing HDL in both genotypes. In WT mice ASO6 led to the appearance of large HDL enriched in apoAI and apoE. The use of ASO6 revealed a new pathway by which the liver may contribute to HDL metabolism in mice. ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1.

Epidemiological studies have consistently demonstrated a positive association between exposure to air pollutants and the incidence of cardiovascular disease, with the strongest evidence for particles with a diameter < 2.5 μm (PM2.5). Therefore, air pollution has been included among the modifiable risk factor for cardiovascular outcomes as cardiovascular mortality, acute coronary syndrome, stroke, heart failure, and arrhythmias. Interestingly, the adverse effects of air pollution are more pronounced at higher levels of exposure but were also shown in countries with low levels of air pollution, indicating no apparent safe threshold. It is generally believed that exposure to air pollution in the long-term can accelerate atherosclerosis progression by promoting dyslipidemia, hypertension, and other metabolic disorders due to systemic inflammation and oxidative stress. Regarding high density lipoproteins (HDL), the impact of air pollution on plasma HDL-cholesterol levels is still debated, but there is accumulating evidence that HDL function can be impaired. In particular, the exposure to air pollution has been variably associated with a reduction in their cholesterol efflux capacity, antioxidant and anti-inflammatory potential, and ability to promote the release of nitric oxide. Further studies are needed to fully address the impact of various air pollutants on HDL functions and to elucidate the mechanisms responsible for HDL dysfunction.

Angiopoietin-like protein 3 (ANGPTL3) is a plasmatic protein that plays a crucial role in lipoprotein metabolism by inhibiting the lipoprotein lipase (LPL) and the endothelial lipase (EL) responsible for the hydrolysis of phospholipids on high-density lipoprotein (HDL). Interest in developing new pharmacological therapies aimed at inhibiting ANGPTL3 has been growing due to the hypolipidemic and antiatherogenic profile observed in its absence. The goal of this study was the in silico characterization of the interaction between ANGPTL3 and EL. Because of the lack of any structural information on both the trimeric coiled-coil N-terminal domain of ANGPTL3 and the EL homodimer as well as data regarding their interactions, the first step was to obtain the three-dimensional model of these two proteins. The models were then refined via molecular dynamics (MD) simulations and used to investigate the interaction mechanism. The analysis of interactions in different docking poses and their refinement via MD allowed the identification of three specific glutamates of ANGPTL3 that recognize a positively charged patch on the surface of EL. These ANGPTL3 key residues, i.e., Glu154, Glu157, and Glu160, could form a putative molecular recognition site for EL. This study paves the way for future investigations aimed at confirming the recognition site and at designing novel inhibitors of ANGPTL3.