Abstract 435: Vascular Gene Therapy with Apolipoprotein A-I in a Rabbit Model of Atherosclerosis Regression

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Bradley K Wacker ◽  
Jingwan Zhang ◽  
Nagadhara Dronadula ◽  
David A Dichek
Keyword(s):  
Gene Therapy ◽  
Lipid Content ◽  
Subgroup Analysis ◽  
Plasma Cholesterol ◽  
Rabbit Model ◽  
Atherosclerotic Lesion ◽  
Chow Diet ◽  
Lesion Volume ◽  
Atherosclerotic Lesions ◽  
Bilateral Carotid

Background: Gene therapy, delivered directly to the vascular wall, could potentially protect against atherosclerotic lesion growth or regress existing lesions. Previously, we demonstrated that use of a helper-dependent adenoviral vector (HDAd) to express apolipoprotein (apo) A-I in carotid endothelium of fat-fed rabbits reduced carotid atherosclerosis measured 4 wk after vector infusion. Here we tested whether the same HDAd could promote atherosclerosis regression when delivered to existing lesions. Methods: To generate atherosclerotic lesions, rabbits were fed a high-fat diet for 4 wk, then underwent bilateral carotid artery surgery with brief intraluminal infusion of DMEM. This protocol yields large lipid- and macrophage-rich lesions within 6 mo. Postoperatively, diets were adjusted to maintain plasma cholesterol of 200 - 800 mg/dl. 6 mo later, rabbits underwent bilateral carotid gene transfer (HDAdApoAI on one side; HDAdNull on the other, with sides randomized) and were changed to chow diet. Carotids were harvested after 3 d (for RNA analysis) and after 7 wk (for analyses of RNA, DNA, and histology). Histologic sections were stained with H&E, oil red O, or antibodies that detect macrophages, smooth muscle actin, ICAM1, and VCAM1. Results: ApoA-I mRNA was detected only in arteries transduced with HDAdApoAI and was present in all HDAdApoAI-infused arteries both at 3 d and 7 wk after infusion. When compared to HDAdNull-infused arteries (n = 26), HDAdApoAI-infused arteries (n = 26) had 30 - 40% less median intimal lesion volume, lipid content, and macrophage content but these differences were not statistically significant (P = 0.3 - 0.9). Post-hoc subgroup analysis of small-to-moderate-sized lesions (n = 20 per group; excluding lesions with volume >1 SD above the mean of all lesions) showed that HDAdApoAI-infused lesions had 50 - 70% less median intimal volume (P = 0.04), lipid content (P = 0.02), and macrophage content (P = 0.03). Conclusions: 7 wk of vascular gene therapy with HDAdApoAI did not consistently cause lesion regression. However, subgroup analysis showed that HDAdApoAI significantly accelerated regression of small-to-moderate-sized atherosclerotic lesions. Prospective testing is required to evaluate the reproducibility of this finding.

Abstract 28: Apolipoprotein A-I Vascular Gene Therapy Provides Durable Protection from Atherosclerosis in Hyperlipidemic Rabbits

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Bradley K Wacker ◽  
Nagadhara Dronadula ◽  
Lianxiang Bi ◽  
Alexis Stamatikos ◽  
David A Dichek
Keyword(s):  
Gene Therapy ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Atherosclerotic Lesion ◽  
Vascular Wall ◽  
Lesion Size ◽  
Lesion Volume ◽  
Bilateral Carotid ◽  
Severe Atherosclerosis

Background: Gene therapy, delivered directly to the vascular wall, could potentially protect against atherosclerotic lesion growth or regress existing lesions. Previously, we demonstrated that infusion of HDAdApoAI [a helper-dependent adenoviral vector (HDAd) expressing apolipoprotein (apo) A-I] in carotid arteries of fat-fed rabbits reduced early carotid atherosclerosis development (4 wk after vector infusion). Here we tested whether the same HDAd could protect long-term against more severe atherosclerosis. Methods: 25 fat-fed rabbits underwent bilateral carotid gene transfer [HDAdApoAI on one side; control vector (HDAdNull) on the other, with sides randomized]. Postoperatively, diets were adjusted to maintain plasma cholesterols of 200-800mg/dl. This protocol yields large lipid- and macrophage-rich lesions. 6 mo later, carotids were harvested for analyses of DNA, RNA, protein, cholesterol, and histology (H&E, oil red O), or immunostaining for macrophages, muscle actin, T-cells, ICAM-1 and VCAM-1. Results: Vector genomes persisted equally in HDAdApoAI and HDAdNull-infused arteries; however, apoA-I mRNA was detected only in HDAdApoAI-infused arteries. HDAdApoAI-infused arteries had ~60% less median intimal lesion volume than HDAdNull-infused arteries, with concomitant reductions (40-75%) in intimal lipid, macrophage, smooth muscle cell, VCAM-1 and ICAM-1. We used within-rabbit paired analyses to control for high correlations of lesion size and composition between left and right carotids of the same rabbit. 19 of 25 rabbits had smaller lesions in HDAdApoAI-infused vs HDAdNull-infused arteries; median decreased intimal area between paired carotids in the same rabbit was 30% ( P <0.03). Within individual rabbits, intimal lipid, macrophage, smooth muscle cell, VCAM-1 and ICAM-1 were all less in HDAdApoAI arteries (median 23-36% less; P <0.05 for all except ICAM-1). Conclusions: Vascular gene therapy with HDAdApoAI reduced lesion development and decreased intimal lipid, macrophage, and adhesion molecule expression 6 mo after treatment. Vector genomes and apo A-I mRNA remained high at 6 mo. A single application of vascular gene therapy durably retards development of atherosclerosis, even in a setting of severe hyperlipidemia.

scholarly journals Vitamin A-Deficient Diet Accelerated Atherogenesis in Apolipoprotein E−/−Mice and Dietaryβ-Carotene Prevents This Consequence

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Noa Zolberg Relevy ◽  
Dror Harats ◽  
Ayelet Harari ◽  
Ami Ben-Amotz ◽  
Rafael Bitzur ◽  
...  
Keyword(s):  
Vitamin A ◽  
Apolipoprotein E ◽  
Vitamin A Deficiency ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Dietary Vitamin ◽  
Control Group ◽  
Chow Diet ◽  
Deficient Diet ◽  
Aortic Sinus

Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE−/−). ApoE−/−mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified withDunaliellapowder containingβc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with aDunaliellapowder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietaryβc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietaryβc, as a sole source of retinoids, can compensate for vitamin A deficiency.

Dried plums (prunes) reduce atherosclerosis lesion area in apolipoprotein E-deficient mice

2008 ◽  
Vol 101 (2) ◽  
pp. 233-239 ◽  
Author(s):  
Cynthia M. Gallaher ◽  
Daniel D. Gallaher
Keyword(s):  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Thiobarbituric Acid ◽  
Basal Diet ◽  
Negative Control ◽  
Lesion Area ◽  
Arterial Tree ◽  
Atherosclerotic Lesions ◽  
Additional Group ◽  
Amyloid P

Dried plums are a fruit high in pectin with substantial antioxidant activity. Previous studies in rats and man indicate that dried plums or plum fibre lower liver and plasma cholesterol, respectively. The apoE-deficient mouse, which develops atherosclerotic lesions rapidly when fed cholesterol, was used to determine the ability of dried plums to reduce atherosclerosis. Diets containing 0·15 % cholesterol and either 0 (B+C), 4·75 % (Lo DP) or 9·5 % (Hi DP) dried plum powder were fed for 5 months. An additional group fed the basal diet without cholesterol (B − C) was included as a negative control. Arterial trees were dissected, stained to visualize lesions, and lesion area was quantitated by imaging software. Urinary thiobarbituric acid-reactive substances (TBARS) excretion and serum amyloid P-component (SAP) were measured as indicators of oxidative stress and inflammation, respectively. Final serum cholesterol was significantly increased and serum TAG decreased in the B+C group and dried plum groups relative to the B − C group. Percentage arterial tree atherosclerotic lesion area was significantly lower in the B − C and Lo DP groups compared to the B+C group (P < 0·05), with a trend for a difference between the B+C and Hi DP groups (P = 0·075). SAP concentration was significantly lower in the B − C and Lo DP groups with the Hi DP group trending lower than the B+C group. Urinary TBARS excretion did not differ among the groups. These results suggest that consuming dried plums may help slow the development of atherosclerosis.

Abstract 409: Is Accelerated Atherosclerosis a Microvascular Complication of Diabetes?

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Heidi K Stoute ◽  
Daniel Venegas-Pino ◽  
Kaley J Veerman ◽  
Geoff H Werstuck
Keyword(s):  
Atherosclerotic Lesion ◽  
Vasa Vasorum ◽  
Lesion Volume ◽  
Lesion Area ◽  
Accelerated Atherosclerosis ◽  
Microvascular Changes ◽  
Atherosclerotic Lesions ◽  
Increased Risk ◽  
Deficient Mice ◽  
Progression Of Atherosclerosis

Introduction: The complications of diabetes have traditionally been categorized as micro- or macrovasculature in nature. Individuals with diabetes are at an increased risk of macrovascular complications, including cardiovascular disease and stroke, and also suffer from microvascular disorders including retinopathy, nephropathy and neuropathy. There is increasing evidence these micro- and macrovascular conditions may be linked. Our objective is to determine if direct effects of hyperglycemia on a specific microvascular bed, the vasa vasorum, promotes diabetes-associated accelerated atherosclerosis. Methods and Results: The effects of hyperglycemia on retinal and vasa vasorum neovascularization and aortic atherogenesis were examined in streptozotocin-injected apolipoprotein-E deficient (ApoE-/-) mice and normoglycemic ApoE-/- controls. Microvessel densities of the retina and vasa vasorum were quantified at 5, 10, 15 and 20 weeks of age. Atherosclerotic lesion volume in the ascending aorta was determined at the same time points. The expression levels of pro-angiogenic factors, VEGF and VEFGR2, were also determined. Data from normoglycemic ApoE-deficient mice indicate that there is an expansion in vasa vasorum density as the atherosclerotic lesion area increases. In contrast, hyperglycemic ApoE-/- mice have significantly larger atherosclerotic lesions (2 fold, P<0..05) but have no detectible neovascularization of the vasa vasorum A deficiency in VEGF expression in the artery walls of the hyperglycemic mice may explain lack of neovascularization. Conclusions: These findings indicate that the microvessel structure of the vasa vasorum is altered by hyperglycaemia. The development and progression of atherosclerosis in hyperglycemic ApoE-deficient mice directly correlates with, and may be influenced by, microvascular changes.

Abstract 068: Endothelin-1 Exaggerates Type-1 Diabetes-accelerated Atherosclerosis Through NADPH Oxidases 1 and 4

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Suellen C Coelho ◽  
Mario F Neves ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Plasma Cholesterol ◽  
Vascular Complications ◽  
Atherosclerotic Lesion ◽  
Fold Increase ◽  
Mesenteric Arteries ◽  
Aortic Sinus ◽  
Accelerated Atherosclerosis ◽  
Plaque Area ◽  
Atherosclerotic Lesions

Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout ( Apoe -/- ) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Methods: Six-week-old male Apoe -/- mice, eET-1/ Apoe -/- and eET-1/ Apoe -/- mice deficient in Nox1 (eET-1/ Apoe -/- / Nox1 y/- ) or Nox4 (eET-1/ Apoe -/- / Nox4 -/- ) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP injections for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Plasma cholesterol, HDL and triglycerides were measured. Results: Diabetic Apoe -/- mice presented an impaired endothelium-dependent vasodilatory response to acetylcholine, which was not observed in diabetic eET-1/ Apoe -/- , eET-1/ Apoe -/- / Nox1 y/- or eET-1/ Apoe -/- / Nox4 -/- mice (E max : 20±6 vs 99±1, 98±1 and 100±0%). ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe -/- mice (5.3±0.3 vs 2.9±0.2%), which was further increased 1.2-fold by Nox4 (6.4±0.3%) but not Nox1 knockout (5.5±0.3%). ET-1 overexpression exaggerated >2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe -/- mice (plaque area [x10 5 μm 2 ]: 5.3±0.5 vs 2.9±0.6), which was reduced ~40% by Nox1 and Nox4 knockout (plaque area [x10 5 μm 2 ]: 3.3±0.6 and 3.6±0.6). Plasma triglycerides were unaffected by ET-1 overexpression but reduced by Nox1 (2.2±0.4 vs 3.4±0.3 mmol/L) and Nox4 knockout (1.8±0.4 mmol/L). Plasma HDL and cholesterol were similar between groups. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.

Maternal high-fat feeding in pregnancy programs atherosclerotic lesion size in the ApoE*3 Leiden mouse

2016 ◽  
Vol 7 (3) ◽  
pp. 290-297 ◽  
Author(s):  
E. J. Tarling ◽  
K. J. P. Ryan ◽  
R. Austin ◽  
S. J. Kugler ◽  
A. M. Salter ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Maternal Diet ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Lesion Size ◽  
Atherogenic Diet ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Cell Proliferation And Differentiation

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat dietin utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat,n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat,n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563,P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers,P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

scholarly journals The peroxisome-proliferator-activated receptor alpha agonist ciprofibrate severely aggravates hypercholesterolaemia and accelerates the development of atherosclerosis in mice lacking apolipoprotein E

2003 ◽  
Vol 373 (3) ◽  
pp. 941-947 ◽  
Author(s):  
Tao FU ◽  
Papreddy KASHIREDDY ◽  
Jayme BORENSZTAJN
Keyword(s):  
Apolipoprotein E ◽  
Plasma Cholesterol ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Very Low Density Lipoproteins ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atherosclerotic Lesions ◽  
Deficient Mice

Mice lacking apolipoprotein E (apoE) are characterized by severe hypercholesterolaemia, caused by an abnormal accumulation of apolipoprotein B-48 (apoB-48)-carrying remnants of chylomicrons and very-low-density lipoproteins (VLDL) in the plasma, and by the spontaneous development of atherosclerotic lesions. Ciprofibrate is a hypolipidaemic compound that acts primarily by enhancing the oxidation of fatty acids in the liver and, consequently, decreasing the production of hepatic VLDL. In the present study, homozygous apoE-deficient mice were fed with a normal chow diet, supplemented with ciprofibrate. We report that, as anticipated, ciprofibrate treatment (a) stimulated hepatic fatty acid oxidation, as indicated by an increase in the mRNA levels of peroxisomal fatty acyl-CoA oxidase (AOX) and peroxisomal bifunctional enzyme, and (b) decreased the hepatic secretion of VLDL into the plasma, as determined by treating the animals with Triton WR-1339. Paradoxically, the apoE-deficient mice developed a 3–4-fold increase in their plasma cholesterol levels. A similar effect was observed in apoE-deficient mice treated with other peroxisome-proliferator-activated receptor α agonists (fenofibrate, bezafibrate and WY14,643). By FPLC of the plasma and Western-blot analysis, we determined that the enhanced hypercholesterolaemia was due to an increased accumulation of apoB-48-carrying lipoprotein remnants in the plasma. Consistent with this finding, atherosclerotic lesions in animals treated with ciprofibrate for 90 days were considerably more advanced than in untreated animals. These results indicate that the ciprofibrate-induced accumulation of apoB-48-carrying remnants in apoE-deficient mice is caused by the inhibition of an as yet uncharacterized apoE-independent mechanism of removal of remnant from the circulation by the liver.

scholarly journals Temporal and Quantitative Analysis of Atherosclerotic Lesions in Diet-Induced Hypercholesterolemic Rabbits

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Qi Yu ◽  
Yafeng Li ◽  
Ahmed Bilal Waqar ◽  
Yanli Wang ◽  
Bingqiao Huang ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Rabbit Model ◽  
Cellular Component ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
High Cholesterol ◽  
Ideal Model ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Transmission Electron

The diet-induced atherosclerotic rabbit is an ideal model for atherosclerosis study, but temporal changes in atherosclerotic development in hypercholesterolemic rabbits are poorly understood. Japanese white rabbits were fed a high-cholesterol diet to induce sustained hypercholesterolemia, and each group of 10–12 animals was then sacrificed at 6, 12, 16, or 28 weeks. The rabbit aortas were harvested, and the sizes of the gross and intima atherosclerotic lesions were quantified. The cellular component of macrophages (Mφs) and smooth muscle cells (SMCs) in aortic intimal lesions was also quantified by immunohistochemical staining, and the correlation between plasma cholesterol levels and the progress of atherosclerotic lesions was studied. The ultrastructure of the atherosclerotic lesions was observed by transmission electron microscopy (TEM). Widely variable atherosclerotic plaques were found from 6 weeks to 28 weeks, and the lesional progress was closely correlated with cholesterol exposure. Interestingly, a relatively reduced accumulation of Mφ, an increased numbers of SMCs, and a damaged endothelial layer were presented in advanced lesions. Moreover, SMCs were closely correlated with cholesterol exposure and lesional progress for the whole period. Cholesterol exposure directly determines atherosclerotic progress in a rabbit model, and the changes in the cellular component of advanced lesions may affect plaque stability in an atherosclerotic rabbit model.

scholarly journals Reduced Atherosclerotic Lesion Size inP-Selectin Deficient ApolipoproteinE-Knockout Mice Fed a Chow but Not a Fat Diet

2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
Marie-Claude Bourdillon ◽  
Jacques Randon ◽  
Lydie Barek ◽  
Kazem Zibara ◽  
Chantal Covacho ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Vascular Lesions ◽  
Chow Diet ◽  
Double Knockout ◽  
Beneficial Effects ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels ◽  
Human Arteries ◽  
Lower Ratio

Endothelial cells lining atherosclerotic, but not healthy sites, on human arteries expressP-selectin. We investigated the role ofP-selectin on the development of vascular lesions in an ApoE−/−male mice. Double-knockout (ApoE−/−,P-selectin-/-; DKO) were compared to single-knockout (ApoE−/−; SKO) mice. They were fed a chow or fat diet for 3, 6, 15, and 20 weeks, without any differences in cholesterol levels. DKO mice fed a chow diet exhibited a ratio of lesion area over media lower than SKO mice, for 3 (P<.03) , 6 (P<.001), and 15 (P<.02) weeks. DKO mice fed a fat diet showed a lower ratio only at 3 weeks.P-selectin deficiency in ApoE−/−mice has a protective effect in atherosclerotic lesions development. Reduction of lesion size depends on diet type and duration. A fat diet could neutralize the beneficial effects ofP-selectin deficiency, inducing atherosclerotic lesions via probably other adhesion molecules.

Abstract 104: Apolipoprotein D: Implications for Multiple Roles in Lipid Metabolism

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ujala Srivastava ◽  
Ehab M Abo-Ali ◽  
Susanna Nguy ◽  
Jean Lebegue ◽  
Kamilah Ali
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Atherosclerotic Lesion ◽  
Minor Component ◽  
Chow Diet ◽  
Lcat Activity ◽  
Wild Type ◽  
Cholesterol Acyl Transferase ◽  
Cholesterol Levels ◽  
Significant Difference

Introduction- ApoD is a ubiquitously expressed protein that binds small hydrophobic ligands and is a minor component of lipoproteins. Polymorphisms of the human ApoD gene are associated with lipid abnormalities, specifically the reduction of HDL and ApoA1 levels. In fact, hepatic overexpression of ApoD has been shown to regulate the amount of plasma triglycerides. ApoD is also upregulated in human and mouse models of atherosclerosis, and is localized in cell types involved in atherosclerotic lesion formation. These data suggest that ApoD plays a role in lipid metabolism by modulating cellular processes in vascular cells during atherogenesis. In this study, our objective is to identify the role(s) of ApoD in lipid metabolism and to elucidate the mechanisms involved in this process. Methods and Results- To accomplish our objective, we used a two-pronged approach. We first studied the effect of ApoD on lipid metabolism on a chow diet. There was no significant difference between the levels of plasma cholesterol in ApoD -/- and wild-type mice on a chow diet; however, hepatic cholesterol levels had more than doubled. A 96-gene PCR array was used to assess differential expression of genes involved in fatty liver biogenesis. There was at least a 2-fold difference in expression in about 10 genes involved in insulin/glucose signaling, lipogenesis, and inflammation in the ApoD -/- mice. We then studied the effect of a Western diet in the ApoD -/- mice, which showed a significant reduction in plasma LDL-cholesterol and HDL-cholesterol when compared to wild-type mice. Analysis of the HDL fractions after subjecting plasma to a Fast Protein Liquid Chromatography column revealed increased levels of ApoA1 and Lecithin Cholesterol Acyl Transferase (LCAT) activity in ApoD -/- mice. Conclusion- A decrease in plasma cholesterol and an increase in ApoA1 and LCAT activity suggest that ApoD may play a role in the catabolism of HDL particles, resulting in lower plasma cholesterol levels in ApoD -/- mice. Our current data implies that ApoD plays a multifunctional role in lipid metabolism and the mechanism by which this occurs must be further examined.

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