RESUMEN
Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered.
Asunto(s)
Apolipoproteína A-I/sangre , Glicoproteínas/deficiencia , Glicoproteínas/genética , Lipoproteínas HDL/sangre , Secuencia de Aminoácidos , Animales , Apolipoproteína A-I/química , Colesterol/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Lipoproteínas HDL/química , Lipoproteínas HDL/metabolismo , Masculino , Ratones , Datos de Secuencia Molecular , Tamaño de la PartículaRESUMEN
Adrenal aldosterone production is regulated by physiological agonists at the level of early and late rate-limiting steps. Numerous studies have focused on the role of lipoproteins including high-density lipoprotein (HDL) as cholesterol providers in this process; however, recent research suggests that HDL can also act as a signaling molecule. Herein, we used the human H295R adrenocortical cell model to study the effects of HDL on adrenal aldosterone production and CYP11B2 expression. HDL, especially HDL2, stimulated aldosterone synthesis by increasing expression of CYP11B2. HDL treatment increased CYP11B2 mRNA in both a concentration- and time-dependent manner, with a maximal 19-fold increase (24 h, 250 µg/ml of HDL). Effects of HDL on CYP11B2 were not additive with natural agonists including angiotensin II or K(+). HDL effects were likely mediated by a calcium signaling cascade, because a calcium channel blocker and a calmodulin kinase inhibitor abolished the CYP11B2-stimulating effects. Of the two subfractions of HDL, HDL2 was more potent than HDL3 in stimulating aldosterone and CYP11B2. Further studies are needed to identify the active components of HDL, which regulate aldosterone production.
Asunto(s)
Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , HDL-Colesterol/farmacología , Citocromo P-450 CYP11B2/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Corteza Suprarrenal/citología , Calcio/metabolismo , Señalización del Calcio/fisiología , Línea Celular , Citocromo P-450 CYP11B2/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Humanos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Depuradores de Clase B/genética , Receptores Depuradores de Clase B/metabolismoRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipolipemiantes , Lípidos/sangre , Lipoproteínas/sangre , PPAR alfa/agonistas , Piperidinas/farmacología , Propionatos/farmacología , Adiponectina/sangre , Animales , Área Bajo la Curva , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/genética , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Macaca fascicularis , Pérdida de Peso/efectos de los fármacosRESUMEN
The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.
Asunto(s)
PPAR alfa/agonistas , PPAR gamma/agonistas , Propionatos/síntesis química , Propionatos/farmacología , Animales , Disponibilidad Biológica , Glucemia/análisis , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Femenino , Insulina/sangre , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Transgénicos , Propionatos/farmacocinética , Ratas , Triglicéridos/sangreRESUMEN
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARalpha agonist is realized.
Asunto(s)
Metabolismo de los Lípidos/fisiología , PPAR alfa/agonistas , Piperidinas/farmacología , Animales , Perfilación de la Expresión Génica , Humanos , Hipolipemiantes/farmacología , Metabolismo de los Lípidos/genética , Hígado , Ratones , Ratones Transgénicos , PPAR alfa/genética , PPAR alfa/metabolismo , Piperidinas/uso terapéuticoRESUMEN
Lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1) is a type-II transmembrane protein that belongs to the C-type lectin family of molecules. LOX-1 acts as a cell surface endocytosis receptor and mediates the recognition and internalization of ox-LDL by vascular endothelial cells. Internalization of ox-LDL by LOX-1 results in a number of pro-atherogenic cellular responses implicated in the development and progression of atherosclerosis. In an effort to elucidate the functional domains responsible for the binding of ox-LDL to the receptor, a series of site-directed mutants were designed using computer modeling and X-ray crystallography to study the functional role of the hydrophobic tunnel present in the LOX-1 receptor. The isoleucine residue (I(149)) sitting at the gate of the channel was replaced by phenylalanine, tyrosine, or glutamic acid to occlude the channel opening and restrict the docking of ligands to test its functional role in the binding of ox-LDL. The synthesis, intracellular processing, and cellular distribution of all mutants were identical to those of wild type, whereas there was a marked decrease in the ability of the mutants to bind ox-LDL. These studies suggest that the central hydrophobic tunnel that extends through the entire LOX-1 molecule is a key functional domain of the receptor and is critical for the recognition of modified LDL.
Asunto(s)
Lipoproteínas LDL/metabolismo , Receptores Depuradores de Clase E/química , Receptores Depuradores de Clase E/metabolismo , Sustitución de Aminoácidos , Animales , Sitios de Unión/genética , Células CHO , Clonación Molecular , Cricetinae , Cricetulus , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Receptores Depuradores de Clase E/genética , TransfecciónRESUMEN
A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.
Asunto(s)
PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos , Administración Oral , Animales , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Obesos , Modelos Moleculares , Estructura Molecular , Fenilpropionatos/síntesis química , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids from triglyceride-rich lipoproteins into HDL. PLTP has been shown to be an important factor in lipoprotein metabolism and atherogenesis. Here, we report that chronic high-fat, high-cholesterol diet feeding markedly increased plasma cholesterol levels in C57BL/6 mice. PLTP deficiency attenuated diet-induced hypercholesterolemia by dramatically reducing apolipoprotein E-rich lipoproteins (-88%) and, to a lesser extent, LDL (-40%) and HDL (-35%). Increased biliary cholesterol secretion, indicated by increased hepatic ABCG5/ABCG8 gene expression, and decreased intestinal cholesterol absorption may contribute to the lower plasma cholesterol in PLTP-deficient mice. The expression of proinflammatory genes (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) is reduced in aorta of PLTP knockout mice compared with wild-type mice fed either a chow or a high-cholesterol diet. Furthermore, plasma interleukin-6 levels are significantly lower in PLTP-deficient mice, indicating reduced systemic inflammation. These data suggest that PLTP appears to play a proatherogenic role in diet-induced hyperlipidemic mice.
Asunto(s)
Hipercolesterolemia/metabolismo , Proteínas de Transferencia de Fosfolípidos/deficiencia , Proteínas de Transferencia de Fosfolípidos/metabolismo , Alimentación Animal , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Hipercolesterolemia/genética , Inflamación/genética , Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Interleucina-6/sangre , Lípidos/sangre , Lípidos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Transferencia de Fosfolípidos/genéticaRESUMEN
Peroxisomal proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that regulates genes involved in lipid metabolism and energy homeostasis. PPAR-alpha activators, including fibrates, have been used to treat dyslipidemia for several decades. In contrast to their known effects on lipids, the pharmacological consequences of PPAR-alpha activation on cardiac metabolism and function are not well understood. Therefore, we evaluated the role that PPAR-alpha receptors play in the heart. Our studies demonstrate that activation of PPAR-alpha receptors using a selective PPAR-alpha ligand results in cardiomyocyte necrosis in mice. Studies in PPAR-alpha-deficient mice demonstrated that cardiomyocyte necrosis is a consequence of the activation of PPAR-alpha receptors. Cardiac fatty acyl-CoA oxidase mRNA levels increased at doses in which cardiac damage was observed and temporally preceded cardiomyocyte degeneration, suggesting that peroxisomal beta-oxidation correlates with the appearance of microscopic injury and cardiac injury biomarkers. Increased myocardial oxidative stress was evident in mice treated with the PPAR-alpha agonists coinciding with increased peroxisomal biomarkers of fatty acid oxidation. These findings suggest that activation of PPAR-alpha leads to increased cardiac fatty acid oxidation and subsequent accumulation of oxidative stress intermediates resulting in cardiomyocyte necrosis.
Asunto(s)
Cardiomiopatías/metabolismo , Metabolismo de los Lípidos , Miocitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Acil-CoA Oxidasa/biosíntesis , Acil-CoA Oxidasa/genética , Animales , Anticolesterolemiantes/farmacología , Biomarcadores/metabolismo , Cardiomiopatías/inducido químicamente , Cardiomiopatías/genética , Cardiomiopatías/patología , Ácido Clofíbrico/farmacología , Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/genética , Lesiones Cardíacas/metabolismo , Lesiones Cardíacas/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología , Necrosis/genética , Necrosis/metabolismo , Necrosis/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , PPAR alfa/agonistas , PPAR alfa/deficiencia , Peroxisomas/metabolismo , Peroxisomas/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
OBJECTIVE: Studies in bone marrow transplanted from ATP-binding cassette transporter A1 (ABCA1)-deficient mice into normal mice provides direct evidence that the absence of leukocyte ABCA1 exerts a marked proatherogenic effect independent of changes in plasma lipids, suggesting that ABCA1 plays a key role in the regulation of cholesterol homeostasis and function of macrophages. Therefore, we examined whether the absence of ABCA1 affects the morphology, properties, and functional activities of macrophages that could be related to the development of atherosclerosis. METHODS AND RESULTS: We conducted a series of experiments in macrophages isolated from Abca1-deficient and wild-type mice and compared several of their properties that are thought to be related to the development of atherosclerosis. Macrophages isolated from Abca1-deficient mice have an increase in cholesterol content, expression of scavenger receptors, and secretion of chemokines, growth factors, and cytokines, resulting in an increased ability to respond to a variety of chemotactic factors. CONCLUSIONS: Our studies indicate that the absence of ABCA1 leads to significant changes in the morphology, properties, and functional activities of macrophages. These changes, together with the proinflammatory condition present in ABCA1-deficient mice and increased reactivity of macrophages to chemotactic factors, play a key role in the development and progression of atherosclerosis.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Aterosclerosis/fisiopatología , Colesterol/metabolismo , Macrófagos Peritoneales/metabolismo , Receptores Depuradores/genética , Transportador 1 de Casete de Unión a ATP , Animales , Aterosclerosis/inmunología , Aterosclerosis/patología , Células Cultivadas , Quimiocinas/metabolismo , Quimiotaxis de Leucocito/fisiología , Femenino , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/patología , Macrófagos Peritoneales/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Mutantes , Microscopía Electrónica , Choque Séptico/inmunología , Choque Séptico/patología , Choque Séptico/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Vacuolas/metabolismo , Vacuolas/ultraestructuraRESUMEN
Since elevated plasma triglycerides (TGs) are an independent cardiovascular risk factor, we have compared the cholesterol efflux potential of sera from asymptomatic hypertriglyceridemic (HTG) type IIb, type IV or normolipidemic (NLP) individuals using two different cell systems. In both type IIb and IV HTG, the efflux of cholesterol from SR-BI-rich Fu5AH cells was similar to that obtained with NLP. The maintenance of efflux efficiency in spite of reduced HDL-cholesterol levels can be mainly attributed to the relative enrichment of HDL with phospholipid. In the J774 macrophage cell system, pretreatment with cAMP, which upregulates ABCA1, induced a markedly higher increase in efflux to type IV sera compared with type IIb or NLP. In addition, type IV sera exhibited two-fold higher pre-beta HDL relative concentration (percentage of total apo AI) compared with NLP. Moreover, positive correlations were established between ABCA1-mediated efflux and the serum pre-beta HDL levels or TG concentrations. Thus, the hyperTGemia is associated with a higher fraction of apo AI recovered as pre-beta HDL which appear to be partly responsible for enhanced efflux obtained upon the cAMP stimulation of J774 cells. In conclusion, we demonstrated for the first time that the ABCA1-expressing J774 cell system is responsive to the percent of apo AI present in human serum as pre-beta HDL. Our results suggest that high-plasma TG, accompanied by low HDL may not result in an impaired cholesterol efflux capacity.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Colesterol/metabolismo , AMP Cíclico/metabolismo , Hipertrigliceridemia/sangre , Macrófagos/metabolismo , Transportadoras de Casetes de Unión a ATP/análisis , Adulto , Anciano , Animales , Transporte Biológico/efectos de los fármacos , Western Blotting , Estudios de Casos y Controles , Movimiento Celular , Células Cultivadas , AMP Cíclico/farmacología , Humanos , Hipertrigliceridemia/diagnóstico , Lipoproteínas HDL/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Probabilidad , ARN Mensajero/análisis , Muestreo , Sensibilidad y Especificidad , Regulación hacia ArribaRESUMEN
Recent studies have demonstrated that the ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of phospholipids and cholesterol to apoprotein acceptors, leading to the synthesis of HDL. The purpose of this study was to determine the changes in the lipoprotein fractions in Abca1-deficient mice and study the mechanisms responsible for the low levels of HDL when ABCA1 is absent. Plasma phospholipid concentration was decreased by more than 75%, mostly due to a reduction of phosphatidylcholine (PC) in HDL. Abca1(-/-) HDL represents less than 2% of wild-type levels and is smaller and enriched in phospholipids (11.2-fold more than HDL from controls). Compared to wild-type littermates, Abca1(-/-) HDL had a 4-fold increase in PC, whereas lysophosphatidylcholine (LPC) (125-fold), sphingomyelin (SPH) (49-fold), and phosphatidylethanolamine (PE) (18-fold) showed even higher increases. As a consequence, the ratios of LPC/PC, SPH/PC, PE/PC, and phosphatidylinositol + phosphatidylserine (PI+PS)/PC were all much higher in HDL from Abca1(-/-), compared to wild-type HDL. Plasma phospholipid transfer protein (PLTP) and lecithin cholesterol acyltransferase (LCAT) activities were decreased by more than 80%, suggesting that the maturation of HDL is affected. To test this hypothesis, plasma from Abca1(-/-) mice was incubated with CHO cells that are known to express high levels of ABCA1 with the intent of restoring the flux of phospholipid and cholesterol onto apoAI. Compared to native plasma, no change in maturation of HDL was observed. In contrast, a 220% increase in the formation of mature HDL was observed when ABCA1 function and LCAT activities were restored. Taken together, these observations suggest that ABCA1 is necessary for the adequate lipidation of apoAI, which enables the interaction with LCAT and subsequent maturation.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Lipoproteínas HDL/genética , Fosfolípidos/sangre , Transportador 1 de Casete de Unión a ATP , Animales , Apolipoproteína A-I/genética , Colesterol/sangre , Mucosa Intestinal/metabolismo , Lipoproteínas/sangre , Lipoproteínas HDL/sangre , Lipoproteínas HDL/química , Hígado/metabolismo , Ratones , Ratones Endogámicos , Ratones Noqueados , ARN Mensajero/genética , Valores de ReferenciaRESUMEN
The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice and LDLR receptor-deficient (LDLr(-/-)) mice. The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE(-/-) and LDLr(-/-) mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation. However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr(-/-) or the apoE(-/-) mice fed a chow or atherogenic diet. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE(-/-). Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.