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Biomedical subjects

Jacques Genest

Publications and source records attributed to Jacques Genest.

At least 37 records · Page 2Linked to original sources
PubMed2005

Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: the Canadian multicentre randomized trial of tacrolimus vs cyclosporine microemulsion.

BACKGROUND: Tacrolimus improves lipid profile in renal and liver transplant recipients. The impact of conversion from cyclosporine microemulsion (Neoral) to tacrolimus (Prograf) in a large randomized study of stable heart transplant recipients with treated but persistent mild dyslipidemia is reported. METHODS: One hundred twenty-nine long-term (>or=12 months) cyclosporine microemulsion-treated heart transplant recipients with low-density lipoprotein cholesterol >2.5 mmol/liter and/or a total cholesterol/high-density lipoprotein cholesterol ratio >4 were recruited for the study. Complete lipid profile was assessed before (baseline) and after 6 months of treatment with either cyclosporine microemulsion maintenance (n=64) or tacrolimus conversion (n=65). RESULTS: At 6 months, tacrolimus-converted patients exhibited a greater decrease in total cholesterol (from 5.51 +/- 0.16 to 4.88 +/- 1.22 mmol/liter [tacrolimus], vs 5.61 +/- 1.36 to 5.38 +/- 0.87 mmol/liter [cyclosporine]; p = 0.0078). This decrease in cholesterol was caused largely by a decrease in low-density lipoprotein cholesterol (-0.41 +/- 0.54 [tacrolimus] vs -0.13 +/- 0.55 [cyclosporine]; p=0.0018). There were no changes in high-density lipoprotein cholesterol and triglyceride levels, but apolipoprotein B therapy was reduced in tacrolimus-converted vs cyclosporine-maintained patients (p=0.0003). By 6 months, 23.7% of tacrolimus- vs 6.7% of cyclosporine-treated patients met the target lipid levels for high-risk patients (p=0.0094). Conversion from cyclosporine to tacrolimus resulted in decreases in blood urea nitrogen, creatinine, and uric acid without any changes in glucose, HbA(1C), and insulin levels. CONCLUSIONS: Conversion from cyclosporine microemulsion- to tacrolimus-based immunoprophylaxis resulted in decreased cholesterol, apolipoprotein B, urea, creatinine, and uric acid without any clinically evident perturbation of glucose metabolism in stable heart transplant recipients with treated but persistent mild dyslipidemia.

Adult↗
PubMed2005

Statin therapy in Canadian patients with hypercholesterolemia: the Canadian Lipid Study -- Observational (CALIPSO).

BACKGROUND: Although statins are widely used to reduce low density lipoprotein cholesterol (LDL-C), there is little information about patient profiles, treatment patterns and goal achievement among statin-treated patients in Canada. OBJECTIVES: To assess the profile of statin-treated patients and to determine whether they are achieving recommended targets for LDL-C. METHODS: The Canadian Lipid Study -- Observational (CALIPSO) was a cross-sectional study involving Canadian physicians who were among the top statin prescribers. Each physician enrolled up to 15 patients who were at least 18 years of age with a diagnosis of hyper-cholesterolemia and who had been using a statin for at least eight weeks. Sociodemographics, coronary artery disease (CAD) risk factors, pretreatment and current lipid levels, and history of lipid-lowering therapy were reported for 3721 patients. RESULTS: Sixty-eight per cent of statin-treated patients were at high CAD risk according to the 2003 Canadian guidelines, 46.4% had established cardiovascular disease, 33.9% had diabetes and 59.5% had hypertension. Average LDL-C reductions of 32% (37% for high-risk patients) were initially required to reach goal. At the study visit, patients had been treated for an average of 4.3 years and 24.2% were using a high statin dose. Despite statin therapy, 27.2% of all patients and 36.4% of those at high CAD risk had not achieved LDL-C targets. For 67.4% of these patients, the current therapy was not modified at the study visit. CONCLUSIONS: Despite effective therapies, many treated patients are not achieving recommended LDL-C targets. Strategies should be implemented to promote achievement of lipid treatment goals for high-risk patients, thereby reducing the risk of cardiovascular events and their associated clinical and economic burdens.

Aged↗
PubMed2004

Cellular physiology of cholesterol efflux in vascular endothelial cells.

BACKGROUND: Of the cells that compose the atherosclerotic plaque, vascular endothelial cells are the most resistant to cholesterol accumulation. Cholesterol efflux pathways may play an important role in endothelial cholesterol homeostasis. METHODS AND RESULTS: We examined the global genetic response of endothelial cells to cholesterol and in particular the contribution of the cholesterol efflux proteins ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor B-I (SR-BI) to endothelial cell cholesterol efflux. The ABCG1 gene is induced in endothelial cells by cholesterol, whereas ABCA1 is not. Using specific chemical inhibitors of ABC transporters and SR-BI, we have shown that neither ABC transporters nor SR-BI is required for apolipoprotein A-1-mediated endothelial cholesterol efflux. CONCLUSIONS: Endothelial cells may use nontraditional pathways for cholesterol efflux.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Characterization of oligomeric human ATP binding cassette transporter A1. Potential implications for determining the structure of nascent high density lipoprotein particles.

The oligomeric structure of ABCA1 transporter and its function related to the biogenesis of nascent apoA-I-containing particles (LpA-I) were investigated. Using n-dodecylmaltoside and perfluoro-octanoic acid combined with non-denaturing gel, the majority of ABCA1 was found as a tetramer in ABCA1-induced human fibroblasts. Furthermore, using chemical cross-linking and SDS-PAGE, ABCA1 dimers but not the tetramers were found covalently linked. Oligomeric ABCA1 was present in isolated plasma membranes as well as in intracellular compartments. Interestingly, apoA-I was found to be associated with both dimeric and tetrameric, but not monomeric, forms of ABCA1. Neither apoA-I nor lipid molecules did affect ABCA1 oligomerization. Immunoprecipitation analysis showed that oligomeric ABCA1 did not contain other associated proteins. We next investigated the relationship between the oligomeric ABCA1 complex and the structure of LpA-I. Lipid-free apoA-I incubated with normal cells generated LpA-I with diameters between 9.5 and 20 nm. Subsequent isolation of LpA-I followed by cross-linking revealed the presence of four and eight apoA-I molecules per particle, whereas apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles and remained in the monomeric form. These results demonstrate that: 1) ABCA1 exists as an oligomeric complex; and 2) ABCA1 oligomerization was independent of apoA-I binding and lipid molecules. The findings that the majority of ABCA1 exists as a tetramer that binds apoA-I, together with the observation that LpA-I contains at least four molecules of apoA-I per particle, support the concept that the homotetrameric ABCA1 complex constitutes the minimum functional unit required for the biogenesis of high density lipoprotein particles.

ATP Binding Cassette Transporter 1↗
PubMed2004

Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus.

The Diabetes Atherosclerosis Intervention Study (DAIS) examined the effects of fenofibrate or placebo on the progression of coronary artery disease (CAD) in 418 type 2 diabetic subjects with dyslipidemia. Fenofibrate use was associated with a 6% increase in high-density lipoprotein cholesterol, a 28% decrease in triglycerides, a 5% decrease in low-density lipoprotein cholesterol, and a 55% increase in plasma homocysteine (tHcy). The purpose of the present study was to determine whether this increase in tHcy in the fenofibrate group was associated with CAD progression or with clinical events. The increase in tHcy with fenofibrate (n = 207) was not related to changes in factors known to modulate tHcy levels (serum levels of Vitamin B(12), folate, or renal function). CAD was quantified by angiography at baseline and after a minimum of 3 years of therapy with fenofibrate or placebo. The primary end point was change in mean segment diameter (MSD), minimal lumen diameter, and percent stenosis. Baseline tHcy level was correlated with percent diameter stenosis (r = 0.111, p = 0.028). Baseline, but not end-of-study elevated tHcy levels, decreased the beneficial effect of fenofibrate. Unexpectedly, the final tHcy levels correlated negatively with CAD progression (r = -0.111, p = 0.031) in the overall group. In the fenofibrate group, there was no significant correlation between tHcy and minimal lumen diameter (r = -0.135, p = 0.069), or percent stenosis. An increase in tHcy levels was not correlated with adverse clinical events in the fenofibrate group. This analysis of the the DAIS reveals that the fenofibrate-mediated increase in tHcy levels does not attenuate the beneficial effects of fenofibrate on CAD progression or clinical events.

Aged↗
PubMed2004

Molecular interactions between apoE and ABCA1: impact on apoE lipidation.

Apolipoprotein E (apoE)/ABCA1 interactions were investigated in human intact fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Here, we show that purified human plasma apoE3 forms a complex with ABCA1 in normal fibroblasts. Lipid-free apoE3 inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than reconstituted HDL particles (IC(50) = 2.5 +/- 0.4 microg/ml vs. 12.3 +/- 1.3 microg/ml). ApoE isoforms showed similar binding for ABCA1 and exhibited identical kinetics in their abilities to induce ABCA1-dependent cholesterol efflux. Mutation of ABCA1 associated with Tangier disease (C1477R) abolished both apoE3 binding and apoE3-mediated cholesterol efflux. Analysis of apoE3-containing particles generated during the incubation of lipid-free apoE3 with stimulated normal cells showed nascent apoE3/cholesterol/phospholipid complexes that exhibited prebeta-electrophoretic mobility with a particle size ranging from 9 to 15 nm, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) cells was unable to form such particles. These results demonstrate that 1). apoE association with lipids reduced its ability to interact with ABCA1; 2). apoE isoforms did not affect apoE binding to ABCA1; 3). apoE-mediated ABCA1-dependent cholesterol efflux was not affected by apoE isoforms in fibroblasts; and 4). the lipid translocase activity of ABCA1 generates apoE-containing high density-sized lipoprotein particles. Thus, ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo.

ATP Binding Cassette Transporter 1↗
PubMed2004

Is the decreased high-density lipoprotein cholesterol in the metabolic syndrome due to cellular lipid efflux defect?

The metabolic syndrome (MS) is associated with cardiovascular disease. The low high-density lipoprotein cholesterol (HDL-C) seen in the MS is associated with increased hepatic secretion of apolipoprotein B-containing lipoproteins. Patients with low HDL-C and abnormal cellular lipid efflux due to ABCA1 gene defects (Tangier disease) also have elevated plasma triglycerides. In the present study, we examined the cellular cholesterol and phospholipid efflux in patients with low HDL-C and features of the MS. Forty-four patients with a HDL-C below the fifth percentile for age and gender were selected. The MS was defined by a low HDL-C and at least two additional features: body mass index at least 30 kg/m(2), plasma triglycerides at least 150 mg/dl, fasting glucose at least 110 mg/dl, and blood pressure at least 130/85 mm Hg. Cellular lipid efflux was examined on fibroblasts obtained from study subjects, nine normal controls and six subjects with Tangier disease. In 22 patients identified with the MS, HDL-C was 21 +/- 7 mg/dl, triglyceride levels were 340 +/- 157 mg/dl, and cellular cholesterol and phospholipid efflux were 107 +/- 18% and 105 +/- 17% of controls, respectively. No patient with the MS and low HDL-C showed a cellular lipid efflux defect. We conclude that primary cellular lipid efflux defects do not contribute to the low HDL-C frequently encountered in the MS.

Adult↗
PubMed2004

High-density lipoproteins: multifunctional vanguards of the cardiovascular system.

The plasma level of high-density lipoprotein (HDL)-cholesterol is inversely correlated with coronary artery disease, the leading cause of death worldwide. HDL particles are thought to mediate the uptake of peripheral cholesterol and, through exchange of core lipids with other lipoproteins or selective uptake by specific receptors, return this cholesterol to the liver for bile acid secretion or hormone synthesis in steroidogenic tissues. HDL particles also act on vascular processes by modulating vasomotor function, thrombosis, cell-adhesion molecule expression, platelet function, nitric oxide release, endothelial cell apoptosis and proliferation. Many of these effects involve signal transduction pathways and gene transcription. Several genetic disorders of HDLs have been characterized at the molecular level. The study of naturally occurring mutations has considerably enhanced understanding of the role of HDL particles. Some mutations causing HDL deficiency are associated with premature coronary artery disease, while others, paradoxically, may be associated with longevity. Modulation of HDL metabolism for therapeutic purposes must take into account, not only the cholesterol content of a particle but its lipid (especially phospholipid) composition, apolipoprotein content, size and charge. Current therapeutic strategies include the use of peroxisome proliferating activator receptor-alpha agonists (fibrates) that increase apolipoprotein AI production and increase lipoprotein lipase activity, statins that have a small effect on HDL-cholesterol but markedly reduce low-density lipoprotein-cholesterol, the cholesterol/HDL-cholesterol ratio and niacin that increases HDL-cholesterol. Potential therapeutic targets include inhibition of cholesteryl ester transfer protein, modulating the ATP-binding cassette A1 transporter, and decreasing HDL uptake by scavenger receptor-B1. Novel therapies include injection of purified apolipoprotien AI and short peptides taken orally, mimicking some of the biological effects of apolipoprotein AI.

Cardiovascular System↗
PubMed2004

Preventive cardiology: move over low density lipoprotein cholesterol, hello C-reactive protein?

The inflammatory marker C-reactive protein (CRP) is a highly promising cardiovascular risk factor. The data associating high sensitivity CRP (hsCRP) to atherosclerotic vascular disease, especially coronary artery disease, are strong, consistent and have been tested across many populations. Multivariate analysis shows that hsCRP has an independent predictive value to the prediction of coronary artery disease along with the conventional cardiovascular risk factors such as sex, age, cigarette smoking, blood pressure, diabetes, elevated total cholesterol (or low density lipoprotein cholesterol) and high density lipoprotein cholesterol. Retrospective analysis of published clinical trials show that individuals with elevated hsCRP benefit from the use of acetylsalicylic acid and/or the statin class of medication. Before implementing a public health policy that includes the measurement and clinical decision-making algorithm using hsCRP, several conditions must be met. Among them, a better understanding of the biology of CRP, an indepth scrutiny at the link between hsCRP levels, the metabolic syndrome, and abdominal obesity and finally, clinical trials, currently underway that will test the hypothesis that patients with elevated levels of hsCRP but a normal low density lipoprotein-cholesterol benefit from a pharmacological intervention for cardiovascular prevention in a primary prevention setting.

Antihypertensive Agents↗
PubMed2003

Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter.

It has been suggested that the signal transduction pathway initiated by apoA-I activates key proteins involved in cellular lipid efflux. We investigated apoA-I-mediated cAMP signaling in cultured human fibroblasts induced with (22R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Treatment of stimulated fibroblasts with apoA-I for short periods of time (<or=45 min) increased ATP binding cassette A1 (ABCA1) phosphorylation in a concentration-dependent manner. Concomitantly, apoA-I increased the intracellular level of cAMP in a concentration- and time-dependent manner. The maximal cAMP level was reached within 10 min at 10 microg/ml apoA-I representing a 1-fold increase. The ability of apoA-I to mediate cAMP production was only observed in stimulated fibroblasts. Furthermore, overexpression of ABCA1 in Chinese hamster ovary cells resulted in a 1.5-fold increase in apoA-I-mediated cAMP accumulation as compared with untransfected cells. In contrast, forskolin increased cAMP production significantly in unstimulated fibroblasts as well as in untransfected Chinese hamster ovary cells. Pharmacological inhibition of protein kinase A (H89) completely blocked apoA-I-mediated ABCA1 phosphorylation. Naturally occurring mutations of ABCA1 associated with Tangier disease (C1477R, 2203X, and 2145X) severely reduced apoA-I-mediated cAMP production, ABCA1 phosphorylation, (125)I-apoA-I binding, and lipid efflux, without affecting forskolin-mediated cAMP elevation. In contrast, the protein kinase A catalytic subunit was able to phosphorylate ABCA1 similarly from mutant and normal cell lines in vitro. Together, our results indicate that apoA-I activates ABCA1 phosphorylation through the cAMP/protein kinase A-dependent pathway, apoA-I-mediated cAMP production required high level expression of functional ABCA1, and Tangier disease mutants have defective apoA-I-mediated cAMP signaling. These findings suggest that apoA-I may activate cAMP signaling through G protein-coupled ABCA1 transporter.

ATP Binding Cassette Transporter 1↗
PubMed2003

Molecular and cellular physiology of apolipoprotein A-I lipidation by the ATP-binding cassette transporter A1 (ABCA1).

The dynamics of ABCA1-mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Specific binding parameters of (125)I-apoA-I to ABCA1 at 37 degrees C were determined: K(d) = 0.65 microg/ml, B(max) = 0.10 ng/microg cell protein. Lipid-free apoA-I inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than pre-beta(1)-LpA-I, reconstituted HDL particles r(LpA-I), or HDL(3) (IC(50) = 0.35 +/- 1.14, apoA-I; 1.69 +/- 1.07, pre-beta(1)-LpA-I; 17.91 +/- 1.39, r(LpA-I); and 48.15 +/- 1.72 microg/ml, HDL(3)). Treatment of intact cells with either phosphatidylcholine-specific phospholipase C or sphingomyelinase affected neither (125)I-apoA-I binding nor (125)I-apoA-I/ABCA1 cross-linking. We next investigated the dynamics of apoA-I lipidation by monitoring the kinetic of apoA-I dissociation from ABCA1. The dissociation of (125)I-apoA-I from normal cells at 37 degrees C was rapid (t((1/2)) = 1.4 +/- 0.66 h; n = 3) but almost completely inhibited at either 15 or 4 degrees C. A time course analysis of apoA-I-containing particles released during the dissociation period showed nascent apoA-I-phospholipid complexes that exhibited alpha-electrophoretic mobility with a particle size ranging from 9 to 20 nm (designated alpha-LpA-I-like particles), whereas lipid-free apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles. These results demonstrate that: 1) the physical interaction of apoA-I with ABCA1 does not depend on membrane phosphatidylcholine or sphingomyelin; 2) the association of apoA-I with lipids reduces its ability to interact with ABCA1; and 3) the lipid translocase activity of ABCA1 generates alpha-LpA-I-like particles. This process plays in vivo a key role in HDL biogenesis.

ATP Binding Cassette Transporter 1↗
PubMed2003

Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency.

BACKGROUND: Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C). METHODS AND RESULTS: We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI-mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia. A phospholipid efflux defect was defined as <70% of controls. Mean HDL-C was 0.49+/-0.21 mmol/L. Cholesterol and phospholipid efflux correlated strongly (r=0.72, P<0.001). Phospholipid efflux and HDL-C (r=0.64, P<0.001) correlated in HypoA subjects. However, phospholipid or cholesterol efflux was no longer a determinant of HDL-C levels at higher levels (> approximately 1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were identified (10 of 64; 16%). In the remaining 54 subjects, mean lipid efflux was not significantly different from controls and subjects with hyperalphalipoproteinemia. A phospholipid efflux defect was identified in 7 additional HypoA subjects, and a cholesterol efflux defect was detected in 11 subjects. In 2 of these subjects, the ABCA1 gene was ruled out as the cause of the efflux defect, while in 3, the low HDL-C trait segregated with the ABCA1 gene locus. CONCLUSIONS: Lipidation of lipid-poor apolipoprotein AI may not be a major determinant of cholesterol accumulation within more mature HDL particles and increasing cholesterol or phospholipid efflux beyond normal levels may not lead to increase in plasma HDL-C levels. ABCA1 is essential in the initial steps of HDL formation but other plasma events are major modulators of HDL-C levels.

ATP Binding Cassette Transporter 1↗
PubMed2003

Structural and functional properties of human plasma high density-sized lipoprotein containing only apoE particles.

To investigate the metabolism of HDL-apolipoprotein E (apoE) particles in human plasma, we isolated a fraction of plasma HDL-apoEs that lack apoA-I (HDL-LpE) from subjects with apoE3/3 phenotype by immunoaffinity. Plasma HDL-LpE had a particle size ranging from 9 nm to 18.5 nm in diameter and was characterized by two-dimensional nondenaturing gradient gel electrophoresis as having either gamma-, prebeta1-, prebeta2-, or alpha-electrophoretic mobility. HDL-LpE was also present in the medium of cultured human hepatoma cell lines and monocyte-derived macrophages. The majority of apoE3 was found as a monomeric form in HDL-LpE and floated at density d > 1.21 g/ml. Plasma levels of HDL-LpE in normolipidemic, CETP-deficient, and ABCA1-deficient subjects were 0.72 +/- 0.15 mg/dl (n = 12), 1.77 +/- 0.75 mg/dl (n = 3), and 0.55 +/- 0.11 mg/dl (n = 3), respectively. The ratio of HDL-apoE containing apoA-I to HDL-LpE was significantly higher 4 h after a fat load, representing a 35 +/- 9% increase (n = 3). Isolated plasma HDL-LpE3 was as effective as apoE3, reconstituted HDL particles, or apoA-I in promoting cellular cholesterol efflux. These results demonstrate that 1) plasma HDL-LpE may have hepatogenous and macrophagic origins; 2) HDL-LpE was preserved even with large reductions in apoA-I-containing lipoproteins; 3) HDL-LpE was active in the transfer of apoE to triglyceride-rich lipoproteins, and 4) HDL-LpEs efficiently take up cell-derived cholesterol.

Apolipoprotein A-I↗
PubMed2003

Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.

Type A and B forms of Niemann-Pick disease (NPD) are lipid storage disorders caused by deficient activity of the enzyme acid sphingomyelinase (aSMase) and the resulting accumulation of sphingomyelin in tissues. In the present study, we investigated two family members who had been diagnosed with Type B NPD and who had a severe decrease in plasma high density lipoprotein cholesterol (HDL-C). The proband (a 48-year-old male) had an HDL-C of 0.30 mmol/l (12 mg/dl) and his sister had values of 0.45 mmol/l (17 mg/dl) with severe premature coronary artery disease (CAD). Hypertriglyceridemia was found in both cases. aSMase activity measured in skin fibroblasts appeared markedly depressed. The SMPD1 gene, coding for aSMase, was sequenced in affected subjects and all family members. Compound heterozygosity (DeltaR608 and R441X) was identified in both affected patients. Carriers of the DeltaR608 mutation tended to have moderately to severe decreased HDL-C levels, whereas carriers of the R441X mutation, although present only in young subjects (<20 years of age) had normal HDL-C levels. To investigate the cause of the low HDL-C level in these patients, we studied apoA-I-mediated cellular cholesterol efflux in fibroblasts. Unlike patients with Tangier disease, cholesterol efflux was found to be normal under the experimental conditions used in the present study. On the other hand, we observed a significant increase in the free cholesterol:esterified cholesterol ratio in HDL fraction from these patients and a decrease in endogenous lecithin-cholesterol acyltransferase (LCAT) activity, as determined by the fractional esterification rate. Taken together, these results suggest that (1) compound heterozygosity at the SMPD1 gene causes a severe decrease in aSMase activity and in HDL-C and increases the risk of CAD, (2) this lipoprotein abnormality is not attributable to defective cellular cholesterol efflux, (3) abnormal HDL composition might cause a decrease in LCAT activity and a lack of HDL maturation.

Cholesterol, HDL↗
PubMed2003

Secretory vesicular transport from the Golgi is altered during ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux.

Apolipoprotein AI (apoAI)-mediated cholesterol efflux is a process by which cells export excess cellular cholesterol to apoAI to form high density lipoprotein. ATP-binding cassette protein A1 (ABCA1) has recently been identified as the key regulator of this process. The pathways of intracellular cholesterol transport during efflux are largely unknown nor is the molecular mechanism by which ABCA1 governs cholesterol efflux well understood. Here, we report that, in both macrophages and fibroblasts, the secretory vesicular transport changes in response to apoAI-mediated cholesterol efflux. Vesicular transport from the Golgi to the plasma membrane increased 2-fold during efflux. This increase in vesicular transport during efflux was observed in both raft-poor and raft-rich vesicle populations originated from the Golgi. Importantly, enhanced vesicular transport in response to apoAI is absent in Tangier fibroblasts, a cell type with deficient cholesterol efflux due to functional ABCA1 mutations. These findings are consistent with an efflux model whereby cholesterol is transported from the storage site to the plasma membrane via the Golgi. ABCA1 may influence cholesterol efflux in part by enhancing vesicular trafficking from the Golgi to the plasma membrane.

ATP Binding Cassette Transporter 1↗