Adipose Modulation of High-Density Lipoprotein Cholesterol (original) (raw)
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objective-Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)-associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown. Methods and Results-Murine HDL was radiolabeled with 125 I in its apolipoprotein and with [ 3 H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)-transgenic (BAC ϩ ) mice and in mice harboring deletions of total (ABCA1 Ϫ/Ϫ ) and liver-specific ABCA1 (ABCA1 ϪL/ϪL ). In BAC ϩ mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1 Ϫ/Ϫ or ABCA1 ϪL/ϪL mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions. Conclusions-Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver. (Arterioscler Thromb Vasc Biol. 2006;26:1821-1827.)
Cardiovascular Research, 2007
Objective: Elevated levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease. The antiatherosclerotic function of HDL is mainly ascribed to its role in reverse cholesterol transport, and requires the integrity of HDL structure. Experimental evidence suggests that the ability of HDL to promote removal of excess cholesterol from peripheral cells is impaired upon oxidation. On the other hand, tyrosylation of HDL enhances its protective function, suggesting that not all forms of modified lipoprotein may be atherogenic. In the present study we investigated the effect of a mild oxidation of HDL 3 on its function as cholesterol acceptor. Methods and results: A mild oxidative stress (induced by 15 min exposure of HDL 3 to 1 μM Cu ++ or to 15-lipoxygenase) caused the formation of pre-β-migrating particles. Compared to native lipoprotein, mildly modified HDL 3 induced a significant ATP-binding cassette transporter 1 (ABCA1)-mediated increase of cholesterol and phospholipids efflux from J774 macrophages. This effect was abolished by an inhibitor of ABCA1-mediated lipid efflux (glyburide) and was absent in Tangier fibroblasts. Conclusions: A mild oxidative modification of HDL 3 may improve its function as cholesterol acceptor, increasing ABCA1-mediated lipid efflux from macrophages, a process that may reduce foam cell formation.
Atherosclerosis, 2001
HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (540 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (PB 0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
A TP-binding cassette transporter A1 (ABCA1) is a key protein determining high-density lipoprotein (HDL) function. In 1999, it was discovered by 3 independent groups that mutations in the gene for ABCA1 underlie the molecular defect in the HDL deficiency syndrome Tangier disease. Subsequent studies with genetically engineered mice lacking or overexpressing ABCA1 provided evidence that ABCA1 modulates atherosclerosis susceptibility on either end of the reverse cholesterol transport pathway. In the liver (and to a lesser extent in intestine), it determines the biogenesis of nascent HDL particles, whereas in macrophages it is essential for the prevention of the excess cholesterol accumulation by facilitating the transport of cellular cholesterol and phospholipid onto lipid-poor apo AI, the major apoprotein of HDL.
HDL and arteriosclerosis: beyond reverse cholesterol transport
Atherosclerosis, 2002
The inverse correlation between serum levels of high density lipoprotein (HDL) cholesterol and the risk of coronary heart disease, the protection of susceptible animals from atherosclerosis by transgenic manipulation of HDL metabolism, and several potentially anti-atherogenic in vitro-properties have made HDL metabolism an interesting target for pharmacological intervention in atheroslcerosis. We have previously reviewed the concept of reverse cholesterol transport, which describes both the metabolism and the classic anti-atherogenic function of HDL (Arterioscler. Thromb. Vasc. Biol. 20 2001 13). We here summarize the current understanding of additional biological, potentially anti-atherogenic properties of HDL. HDL inhibits the chemotaxis of monocytes, the adhesion of leukocytes to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, complement activation, platelet activation and factor X activation but also stimulates the proliferation of endothelial cells and smooth muscle cells, the synthesis of prostacyclin and natriuretic peptide C in endothelial cells, and the activation of proteins C and S. These anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities are exerted by different components of HDL, namley apolipoproteins, enzymes, and even specific phospholipids. This complexity further emphasizes that changes in the functionality of HDL rather than changes of plasma HDL-cholesterol levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism.
Genetic Etiology of Isolated Low HDL Syndrome: Incidence and Heterogeneity of Efflux Defects
Arteriosclerosis, Thrombosis, and Vascular Biology, 2007
Objective-We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. Methods and Results-We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. Conclusions-Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
High-density lipoproteins (HDL) protect against cardiovascular disease. HDL removes and transports excess cholesterol from peripheral cells to the liver for removal from the body. HDL also protects low-density lipoproteins (LDL) from oxidation and inhibits expression of adhesion molecules in endothelial cells, preventing monocyte movement into the vessel wall. The ABCA1 transporter regulates intracellular cholesterol levels in the liver and in peripheral cells by effluxing excess cholesterol to lipid-poor apoA-I to form nascent HDL, which is converted to mature ␣-HDL by esterification of cholesterol to cholesteryl esters (CE) by lecithin cholesterol acyltransferase. The hepatic ABCA1 transporter and apoA-I are major determinants of levels of plasma ␣-HDL cholesterol as well as poorly lipidated apoA-I, which interact with ABCA1 transporters on peripheral cells in the process of reverse cholesterol transport. Cholesterol in HDL is transported directly back to the liver by HDL or after transfer of CE by the cholesteryl ester transfer protein (CETP) by the apoB lipoproteins. Current approaches to increasing HDL to determine the efficacy of HDL in reducing atherosclerosis involve acute HDL therapy with infusions of apoA-I or apoA-I mimetic peptides and chronic long-term therapy with selective agents to increase HDL, including CETP inhibitors. (Arterioscler Thromb Vasc Biol. 2004;24:1755-1760.) Key Words: ABCA1 transporter Ⅲ cholesterol Ⅲ cholesteryl ester transfer protein Ⅲ cholesteryl ester transfer protein inhibitor Ⅲ apoA-I
Atherosclerosis, 2003
ATP-binding cassette transporter A1 (ABCA1) transports cellular cholesterol to lipid-poor apolipoproteins. Mutations in the ABCA1 gene are linked to rare phenotypes, familial hypoalphalipoproteinemia (FHA) and Tangier disease (TD), characterized by markedly decreased plasma high-density lipoprotein cholesterol (HDL-C) levels. The aim was to test if the ABCA1 locus is a major locus regulating HDL-C levels in the homogenous Finnish population with a high prevalence of coronary heart disease (CHD). Firstly, the ABCA1 locus was tested for linkage to HDL-C levels in 35 families with premature CHD and low HDL-C levels. Secondly, 62 men with low HDL-C levels and CHD were screened for the five mutations known to cause FHA. Thirdly, polymorphisms of the ABCA1 gene were tested for an association with HDL-C levels in a population sample of 515 subjects. The ABCA1 locus was not linked to HDL-C levels in the CHD families, and no carriers of the FHA mutations were found. The AA596 genotype was associated with higher HDL-C levels compared with the GG and GA genotypes in the women, but not in the men. The G596A genotypes explained 4% and the A2589G genotypes 3% of the variation in plasma HDL-C levels in women. The data suggest that the ABCA1 locus is of minor importance in the regulation of HDL-C in Finns.