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Reverse Cholesterol Transport (reverse + cholesterol_transport)

Distribution by Scientific Domains

Medical Sciences	91%

Selected Abstracts

Both the Peroxisome Proliferator-Activated Receptor , Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol

CLINICAL AND TRANSLATIONAL SCIENCE, Issue 2 2009
François Briand Ph.D.
Abstract Peroxisome proliferator-activated receptor , (PPAR,) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARÔ activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol-loaded/3H-cholesterol-labeled macrophages injected intraperitoneally. PPARÔ agonist GW0742 (10 mg/kg per day) did not change 3H-tracer plasma appearance, but increased fecal 3H-free sterols excretion by 103% (p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H-cholesteryl ether or 3H-cholesteryl oleate was also measured. While 3H-cholesteryl ether tissue uptake was unchanged, the 3H-tracer recovered in fecal free sterol fraction after 3H-cholesteryl oleate injection increased by 88% with GW0742 (p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine (p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages or HDL injection. In conclusion, PPARÔ activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe. [source]

Reverse cholesterol transport in type 2 diabetes mellitus

DIABETES OBESITY & METABOLISM, Issue 6 2009
K. C. B. Tan
High-density lipoprotein (HDL) plays an important protective role against atherosclerosis, and the anti-atherogenic properties of HDL include the promotion of cellular cholesterol efflux and reverse cholesterol transport (RCT), as well as antioxidant, anti-inflammatory and anticoagulant effects. RCT is a complex pathway, which transports cholesterol from peripheral cells and tissues to the liver for its metabolism and biliary excretion. The major steps in the RCT pathway include the efflux of free cholesterol mediated by cholesterol transporters from cells to the main extracellular acceptor HDL, the conversion of free cholesterol to cholesteryl esters and the subsequent removal of cholesteryl ester in HDL by the liver. The efficiency of RCT is influenced by the mobilization of cellular lipids for efflux and the intravascular remodelling and kinetics of HDL metabolism. Despite the increased cardiovascular risk in people with type 2 diabetes, current knowledge on RCT in diabetes is limited. In this article, abnormalities in RCT in type 2 diabetes mellitus and therapeutic strategies targeting HDL and RCT will be reviewed. [source]

Metabolism of high density lipoprotein apolipoprotein A-I and cholesteryl ester in insulin resistant dog: a stable isotope study

DIABETES OBESITY & METABOLISM, Issue 1 2007
F. Briand
Aims:, In reverse cholesterol transport (RCT), hepatic Scavenger Receptor class B type I (SR-BI) plays an important role by mediating the selective uptake of high-density lipoprotein cholesteryl ester (HDL-CE). However, little is known about this antiatherogenic mechanism in insulin resistance. HDL-CE selective uptake represents the main process for HDL-CE turnover in dog, a species lacking cholesteryl ester transfer protein activity. We therefore investigate the effects of diet induced insulin resistance on RCT. Methods:, Five beagle dogs, in healthy and insulin resistant states, underwent a primed constant infusion of [1,213C2]acetate and [5,5,5- 2H3]leucine, as labelled precursors of CE and apolipoprotein (apo) A-I, respectively. Data were analysed using modelling methods. Results:, HDL-apo A-I concentration did not change in insulin resistant state but apo A-I absolute production rate (APR) and fractional catabolic rate (FCR) were both higher (2.2- and 2.4-fold, respectively, p < 0.05). HDL-CE levels were lower (1.2-fold, p < 0.05). HDL-CE APR and FCR were both lower (2.3- and 2-fold, respectively, p < 0.05), as well as selective uptake (2.6-fold, p < 0.05). Conclusions:, Lower HDL-CE selective uptake suggests that RCT is impaired in obese insulin resistant dog. [source]

Impaired efflux of cholesterol from aged cells and its molecular mechanism: A basis for age-related enhancement of atherosclerosis

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2007
Shizuya Yamashita
Aging is one of the risk factors for atherosclerotic cardiovascular diseases, however, its molecular mechanism is currently unknown. Many types of cells in the atherosclerotic lesions are considered to have various biological abnormalities such as impaired lipid homeostasis and slow cell proliferation, which may be related to senescence at cellular levels. One of the common characteristics of senescent cells in vitro is the alteration of actin cytoskeletons, which were reported to be involved in the intracellular transport of lipids. Cholesterol efflux from the cells is the initial step of reverse cholesterol transport, a major protective system against atherosclerosis. Recently, we demonstrated that Cdc42, a member of the Rho -GTPase family, might be crucial for cellular lipid transport and cholesterol efflux based upon studies of Tangier cells that are deficient in ABCA1 gene. In the current review, we also indicate that the expression of Cdc42 is decreased in the cells from aged subjects in close association with the retarded intracellular lipid transport. Furthermore, the Cdc42 expression is reduced by culturing fibroblasts in vitro for a long duration. Werner syndrome (WS) is characterized by the early onset of senescent phenotypes including premature atherosclerotic cardiovascular diseases, although the underlying molecular mechanism for the enhanced atherosclerosis has not been fully understood yet. We examined the intracellular lipid transport and cholesterol efflux and the expression levels of cholesterol efflux-related molecules in skin fibroblasts obtained from patients with WS. Cholesterol efflux was markedly reduced in the WS fibroblasts in association with an increased cellular cholesterol content. Fluorescent recovery after photobleaching technique revealed that intracellular lipid transport around Golgi apparatus was markedly reduced when using a C6-NBD-ceramide as a tracer. Cdc42 protein and its guanosine 5,-triphosphate-bound active form were markedly reduced in the WS fibroblasts. The adenovirus-mediated complementation of wild-type Cdc42 corrected the impaired cholesterol efflux, intracellular lipid transport and cellular cholesterol levels in the WS fibroblasts. These data indicate that the reduced expression of Cdc42 might be responsible for the abnormal lipid transport, which in turn might be related to the accelerated cardiovascular manifestations in WS patients. The current review focuses on the impaired efflux of cholesterol from aged cells and its molecular mechanism as a basis for age-related enhancement of atherosclerosis. [source]

P2Y13 receptor is critical for reverse cholesterol transport,

HEPATOLOGY, Issue 4 2010
Aurélie C. Fabre
A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote "reverse cholesterol transport" (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y13 (purinergic receptor P2Y, G protein,coupled, 13) activation is essential for HDL uptake but the potential of P2Y13 as a target to promote RCT has not been documented. Here, we show that P2Y13 -deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y13 -deficient mice. Furthermore, cangrelor, a partial agonist of P2Y13, stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BI,knockoutliver) but had no effect in P2Y13 knockout mice, which indicate that P2Y13 -mediated HDL uptake pathway is independent of SR-BI,mediated HDL selective cholesteryl ester uptake. Conclusion: These results establish P2Y13 as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT. (HEPATOLOGY 2010) [source]

Phosphatidylethanol Mediates its Effects on the Vascular Endothelial Growth Factor via HDL Receptor in Endothelial Cells

ALCOHOLISM, Issue 2 2009
Marja Katriina Liisanantti
Background:, Previous epidemiological studies have shown that light to moderate alcohol consumption has protective effects against coronary heart disease but the mechanisms of the beneficial effect of alcohol are not known. Ethanol may increase high density lipoprotein (HDL) cholesterol concentration, augment the reverse cholesterol transport, or regulate growth factors or adhesion molecules. To study whether qualitative changes in HDL phospholipids mediate part of the beneficial effects of alcohol on atherosclerosis by HDL receptor, we investigated whether phosphatidylethanol (PEth) in HDL particles affects the secretion of vascular endothelial growth factor (VEGF) by a human scavenger receptor CD36 and LIMPII analog-I (CLA-1)-mediated pathway. Methods:, Human EA.hy 926 endothelial cells were incubated in the presence of native HDL or PEth-HDL. VEGF concentration and CLA-1 protein expression were measured. Human CLA-1 receptor-mediated mechanisms in endothelial cells were studied using CLA-1 blocking antibody and protein kinase inhibitors. Results:, Phosphatidylethanol-containing HDL particles caused a 6-fold increase in the expression of CLA-1 in endothelial cells compared with the effect of native HDL. That emergent effect was mediated mainly through protein kinase C and p44/42 mitogen-activated protein kinase pathways. PEth increased the secretion of VEGF and that increase could be abolished by a CLA-1 blocking antibody. Conclusions:, High density lipoprotein particles containing PEth bind to CLA-1 receptor and thereby increase the secretion of VEGF from endothelial cells. Ethanol-induced protective effects against coronary heart disease may be explained, at least partly, by the effects of PEth-modified HDL particles on VEGF via CLA-1-mediated mechanisms in endothelial cells. [source]

HDL2 of Heavy Alcohol Drinkers Enhances Cholesterol Efflux From Raw Macrophages via Phospholipid-Rich HDL2b Particles

ALCOHOLISM, Issue 6 2008
Sanna M. Mäkelä
Background:, Alcohol consumption is associated with increased serum high density lipoprotein (HDL) cholesterol levels and a decreased risk for the development of atherosclerosis. However, the effects of heavy alcohol intake on reverse cholesterol transport, one of the key anti-atherogenic processes related to HDL, are poorly known. Methods:, The ability of total HDL as well as HDL2 and HDL3 subclasses to promote cholesterol efflux from 3H-cholesterol-labeled RAW 264.7 macrophages was studied among 6 heavy alcohol drinkers and 6 controls. Distribution of HDL subclasses was analyzed by 4 to 30% native gradient gels. Serum phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities were analyzed among several other biochemical measures. Results:, Cholesterol efflux to HDL2 of heavy drinkers was 22% (p = 0.025) higher relative to controls. The increase in HDL2 phospholipids, with a concomitant 2-fold (p = 0.055) increase in large HDL2b particles, was associated with enhanced cholesterol efflux to HDL2. Interestingly, the cholesterol efflux to HDL3 did not differ between the 2 study groups. These findings may be partially explained by a decreased CETP activity (,26%, p = 0.037) and an increased PLTP activity (39%, p = 0.045) in heavy drinkers. Conclusions:, The increased cholesterol efflux potential of HDL2 is most likely an anti-atherogenic feature linked to heavy alcohol consumption. The cholesterol efflux and HDL phospholipids also associated strongly within the whole study group (rs = 0.910, p , 0.01) suggesting a common pathway of enhanced cholesterol efflux via enlarged phospholipid-rich HDL particles. [source]

Apolipoproteins and , Amyloid Transport Pathway

PSYCHOGERIATRICS, Issue 3 2002
Kouzin Kamino
Abstract: Cholesterol metabolism has been viewed as an important step in the development of Alzheimer's disease, since it was shown that the ,4 allele of apolipoprotein E (APOE) gene is a genetic risk and modifies age-at-onset of Alzheimer's disease. Although the knowledge of the effect of cholesterol in the neuronal cell has been recently accumulated, the link between systemic and brain cholesterol metabolism remains to be elucidated. Lipoproteins in cerebrospinal fluid (CSF) are fractionated only to high-density lipoprotein (HDL), and contain apolipoprotein (apo) A-I, E, A-II, and J. Whereas apoE is produced in the brain, apoA-I and apoA-II in cerebrospinal fluid, the major components of plasma HDL cholesterol, originate from plasma. Plasma HDL is thought to act in reverse cholesterol transport, and in vitro experiments indicated that these apolipoproteins and albumin show a high affinity binding to , amyloid. In patients with Alzheimer's disease, plasma apoA-I and apoA-II levels are significantly decreased, which is possibly related to the deposition of , amyloid in the brain, and to the , amyloid transport pathway. [source]

Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non-Fatal Myocardial Infarction

ANNALS OF HUMAN GENETICS, Issue 6 2008
V. Meiner
Summary Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP ,2708 G/A, ,971 A/G, ,629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (,2708 G, ,971 G, ,629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (,2708 G, ,971 A, ,629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4,14.8] and haplotype B (,2708 G, ,971 G, ,629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 , 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations. [source]

Both the Peroxisome Proliferator-Activated Receptor , Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol

Comparison of high-density and low-density lipoprotein cholesterol subclasses and sizes in asian indian women with caucasian women from the framingham offspring study

CLINICAL CARDIOLOGY, Issue 5 2005
Narendra C. Bhalodkar M.D.
Abstract Background: Asian Indian women have a higher rate of coronary artery disease (CAD) than do other ethnic groups, despite similar conventional risk factors and lipid profiles. Smaller high-density lipoprotein cholesterol (HDL-C) particle size is associated with reduced cardiac protection or even an increased risk of CAD. Exceptional longevity correlates better with larger HDL-C particle sizes. Hypothesis: Higherrates of CAD among Asian Indian women may partly be explained by the differenes in the prevalence of atherogenic HDL-C and low-density lipoprotein cholesterol (LDL-C) sizes and their subclass concentrations among Asian Indian women compared with Caucasian women. Methods: We measured HDL-C concentrations and sizes by nuclear magnetic resonance spectroscopy in 119 relatively healthy Asian Indian women and compared them with those of 1,752 Caucasian women from the Framingham Off spring Study (FOS). Results: Asian Indian women were significantly younger (47.9 ± 11.2 vs.51.0 ± 10.1 years, p = 0.0001), leaner (body mass index 24.0 ± 4.7 vs. 26.0 ± 5.6, p = <0.0002), less likely to be postmenopausal (32 vs. 54%, p =< 0.0001), or smoke (< 1 vs. 20%, p = < 0.0001);nevertheless, prevalence of CAD was higher in Asian Indian women (4.2 vs. 1%, p = 0.0006). Asian Indian women had similar HDL-C (53 ±13 vs. 53 ± 13 mg/dl, p = 0.99), smaller HDL-C particle size (8.9 ± 0.35 vs. 9.4 ± 0.44 nm, p = < 0.0001), highertotal cholesterol (209 ± 40 vs. 199 ± 42 mg/dl, p = 0.01), and similar triglyceride (120 ± 77 vs. 108 ± 110 mg /d, p = 0.24) levels. Low-density lipoprotein cholesterol, particle concentrations and sizes, as well as prevalence of pattern B were similar. Conclusions: Compared with the FOS, Asian Indian women have significantly smaller overall HDL particle size and similar levels of HDL-C, which may reflect impaired, reverse cholesterol transport. Total cholesterol was higher, whereas triglyceride and LDL-C levels were similar. This may partly explain the higher CAD rates in Asian Indian women. Further large scale, prospective, long-term studies are warranted. [source]