Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes

Clee, Susanne M.; Kastelein, J.J.P.; Dam, Marjel van; Marcil, Michel; Roomp, Kirsten; Zwarts, K.Y.; Collins, Jennifer A.; Roelants, Roosje; Tamasawa, Naoki; Štulc, Tomáš; Suda, Toshio; Češka, R.; Boucher, Betsie; Rondeau, C.; DeSouich, C; Brooks‐Wilson, Angela; Molhuizen, H.O.F.; Frohlich, J.; Genest, Jacques; Hayden, Michael R.

doi:10.1172/jci10727

Cited by 300 publications

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“…In humans, the mutation in ABCA1 is the cause of Tangier disease and familial hypoalphalipoproteinemia. The impaired cholesterol efflux from peripheral tissues leads to the defect in generation of nascent HDL and the presence of macrophage/foam cells throughout the body (33). In addition, patients suffer from hepatosplenomegaly, peripheral neuropathy, and frequently premature coronary heart disease (16,33).…”

Section: Discussionmentioning

confidence: 99%

“…The impaired cholesterol efflux from peripheral tissues leads to the defect in generation of nascent HDL and the presence of macrophage/foam cells throughout the body (33). In addition, patients suffer from hepatosplenomegaly, peripheral neuropathy, and frequently premature coronary heart disease (16,33). In animal models, genetic deletion of ABCA1 results in the pathophysiologic conditions similar to those found in Tangier disease patients, such as reduced plasma cholesterol levels, which is mainly due to decreased HDL levels and the accumulation of lipid-laden macrophage/foam cells (34).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Zhou

Yin

Guo

et al. 2010

Journal of Biological Chemistry

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ATP-binding cassette transporter A1 (ABCA1), a molecule mediating free cholesterol efflux from peripheral tissues to apoAI and high density lipoprotein (HDL), inhibits the formation of lipid-laden macrophage/foam cells and the development of atherosclerosis. ERK1/2 are important signaling molecules regulating cellular growth and differentiation. The ERK1/2 signaling pathway is implicated in cardiac development and hypertrophy. However, the role of ERK1/2 in the development of atherosclerosis, particularly in macrophage cholesterol homeostasis, is unknown. In this study, we investigated the effects of ERK1/2 activity on macrophage ABCA1 expression and cholesterol efflux. Compared with a minor effect by inhibition of other kinases, inhibition of ERK1/2 significantly increased macrophage cholesterol efflux to apoAI and HDL. In contrast, activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression. The increased cholesterol efflux by ERK1/2 inhibitors was associated with the increased ABCA1 levels and the binding of apoAI to cells. The increased ABCA1 by ERK1/2 inhibitors was due to increased ABCA1 mRNA and protein stability. The induction of ABCA1 expression and cholesterol efflux by ERK1/2 inhibitors was concentration-dependent. The mechanism study indicated that activation of liver X receptor (LXR) had little effect on ERK1/2 expression and activation. ERK1/2 inhibitors had no effect on macrophage LXR␣/␤ expression, whereas they did not influence the activation or the inhibition of the ABCA1 promoter by LXR or sterol regulatory element-binding protein (SREBP). However, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression. Our data suggest that ERK1/2 activity can play an important role in macrophage cholesterol trafficking.Development of atherosclerotic lesions in coronary arteries is an underlying cause of coronary heart disease. Lipid-laden macrophage/foam cells are a prominent part of atherosclerotic lesions (1). Cellular cholesterol content in macrophages is determined by uptake and efflux of cholesterol (2). The type A scavenger receptor and type B scavenger receptor (CD36) mediate the binding and internalization of modified low density lipoprotein (LDL), 3 thus, demonstrating pro-atherogenic properties (3, 4). In contrast, type BI scavenger receptor and ATPbinding cassette transporter A1 (ABCA1) can mediate cellular free cholesterol efflux to extracellular high density lipoprotein (HDL) or lipid-free apolipoprotein AI (apoAI) thereby inhibiting the development of atherosclerosis (5, 6). Compared with bi-directional cholesterol transport across cellular membranes that are mediated by type BI scavenger receptor (7, 8), ABCA1 stimulates free cholesterol efflux from macrophages and other peripheral cell types to apoAI and/or HDL by using the energy from ATP hydrolysis (9). The binding of free cholesterol and phospholipids to apoAI also leads to the generation of nascent HDL (10). ABCA1 can also mediate cholesterol efflux to exog...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Zhou

Yin

Guo

et al. 2010

Journal of Biological Chemistry

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“…The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9). Clee et al (8) reported an inverse relationship between dysfunctional ABCA1 alleles and plasma TG concentrations. In addition, data from case reports of 59 Tangier patients show variable TG concentrations, with mean, median, minimum, and maximum concentrations of 210, 175, 40, and 580 mg/dl, respectively (4).…”

Section: Abca1 (Atp-binding Cassette Transporter A1) Is Indispensablementioning

confidence: 99%

“…Mutations in ABCA1 in humans cause Tangier disease (TD), an autosomal recessive disorder characterized by severe HDL deficiency, rapid plasma clearance of HDL and apoA-I, sterol deposition in tissues, and premature coronary atherosclerosis (4 -7). In addition to HDL deficiency, TD subjects have significantly elevated plasma TG and a 50% reduction in LDL cholesterol concentrations (4,8). The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9).…”

mentioning

confidence: 99%

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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Loss of ABCA1 activity in Tangier disease (TD) is associated with abnormal apoB lipoprotein (Lp) metabolism in addition to the complete absence of high density lipoprotein (HDL). We used hepatocyte-specific ABCA1 knock-out (HSKO) mice to test the hypothesis that hepatic ABCA1 plays dual roles in regulating Lp metabolism and nascent HDL formation. HSKO mice recapitulated the TD lipid phenotype with postprandial hypertriglyceridemia, markedly decreased LDL, and near absence of HDL. Triglyceride (TG) secretion was 2-fold higher in HSKO compared with wild type mice, primarily due to secretion of larger TG-enriched VLDL secondary to reduced hepatic phosphatidylinositol 3-kinase signaling. HSKO mice also displayed delayed clearance of postprandial TG and reduced post-heparin plasma lipolytic activity. In addition, hepatic LDLr expression and plasma LDL catabolism were increased 2-fold in HSKO compared with wild type mice. Last, adenoviral repletion of hepatic ABCA1 in HSKO mice normalized plasma VLDL TG and hepatic phosphatidylinositol 3-kinase signaling, with a partial recovery of HDL cholesterol levels, providing evidence that hepatic ABCA1 is involved in the reciprocal regulation of apoB Lp production and HDL formation. These findings suggest that altered apoB Lp metabolism in TD subjects may result from hepatic VLDL TG overproduction and increased hepatic LDLr expression and highlight hepatic ABCA1 as an important regulatory factor for apoB-containing Lp metabolism. ABCA1 (ATP-binding cassette transporter A1) is indispensable in the initial steps of high density lipoprotein (HDL)2 formation and the process of reverse cholesterol transport from peripheral tissues to the liver. ABCA1 is expressed in many cells; however, hepatocytes make the single most important contribution to plasma HDL concentration (1-3). Mutations in ABCA1 in humans cause Tangier disease (TD), an autosomal recessive disorder characterized by severe HDL deficiency, rapid plasma clearance of HDL and apoA-I, sterol deposition in tissues, and premature coronary atherosclerosis (4 -7). In addition to HDL deficiency, TD subjects have significantly elevated plasma TG and a 50% reduction in LDL cholesterol concentrations (4,8). The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9). Clee et al. (8) reported an inverse relationship between dysfunctional ABCA1 alleles and plasma TG concentrations. In addition, data from case reports of 59 Tangier patients show variable TG concentrations, with mean, median, minimum, and maximum concentrations of 210, 175, 40, and 580 mg/dl, respectively (4). The underlying mechanisms for the increased plasma TG and decreased LDL concentrations in TD subjects have not been established. In one study, apoA-II enrichment of VLDL of TD subjects was proposed to result in reduced reactivity of VLDL with lipoprotein lipase (LPL) (9, 10). Another study suggested that ABCA1-dependent cholesterol efflux decreases VLDL secretion from murine hep...

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“…Individuals heterozygous for ABCA1 transporter mutations have diminished UC efflux to apo A-I from their fibroblasts in cell culture, low plasma HDL-cholesterol, and premature CHD (18,24 ). These findings have established that inefficient RCT by HDLs is a causal factor in atherogenesis in such individuals.…”

mentioning

confidence: 96%

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

Hashimoto¹,

Kujiraoka²,

Egashira³

et al. 2004

Clinical Chemistry

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Background:In individuals heterozygous for ABCA1 transporter mutations, defective reverse cholesterol transport (RCT) causes low HDL-cholesterol and premature coronary heart disease (CHD). However, the extent to which impaired RCT underlies premature CHD in others with low HDL-cholesterol is not known. The primary acceptors of cell cholesterol are a minor subclass of lipid-poor pre-␤-HDLs. These are generated during remodeling of ␣-HDLs, which account for almost all HDL-cholesterol. We studied the strength of the association of CHD with pre-␤-HDL concentrations in Japanese men. Methods: Blood was collected from 42 men with clinical CHD and 44 healthy controls 40 -70 years of age. Pre-␤-HDL was assayed by crossed immunoelectrophoresis. Results: Cases had lower HDL-cholesterol (؊23%), total apolipoprotein A-I (؊26%), and pre-␤-HDL (؊55%; all P <0.001) concentrations; lower pre-␤-HDL:␣-HDL ratios (؊45%; P <0.001); and higher plasma triglycerides (20%; P <0.03) than the controls. On stepwise logistic regression, CHD was associated most strongly with pre-␤-HDL concentrations. On ROC analysis, pre-␤-

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Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes

Cited by 300 publications

References 35 publications

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

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