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.

Abstract 463: TLT-1 Deficiency Affects Hypercholesterolemia and Progression of the Atherosclerotic Plaque in Apoe Null Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Marieli Gonzalez ◽  
Fiorella Reyes ◽  
Deborah Marrero ◽  
A V Washington
Keyword(s):  
Platelet Activation ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Chow Diet ◽  
Fatty Streak ◽  
Wild Type ◽  
Platelet Surface ◽  
Cholesterol Levels

Platelet activation at sites of inflammation triggers the secretion of molecules that induce the transition of atherosclerosis from fatty streak to an acute disease, featuring an increased vulnerability of the atherosclerotic lesion that results in plaque rupture and thrombosis. TLT-1 (Triggering Receptor Expressed in Myeloid cells (TREM)-like transcript-1) is a molecule exclusively found in the α-granules of megakarocytes and platelets and has a demonstrated effect in inflammatory responses. Upon platelet activation, TLT-1 is moved to the platelet surface, while its soluble form, s-TLT-1, is secreted and detected in serum. Studies using the C57Bl/6 treml1 - /- mouse demonstrated a predisposition to hemorrhage after an acute inflammatory challenge suggesting that TLT-1 may be a key regulatory molecule in the interface between hemostatic and inflammatory mechanisms. Because we have found that sTLT-1 levels are significantly elevated in apoE mice when compared to wild type, we hypothesized that TLT-1 may be playing an important role in the progression of atherosclerosis. To address this possibility, we generated apoE - /- / treml1 - /- double knockout mice [DN]. Assessment of lesions after 4 weeks high-fat diet (HFD) demonstrated that at early stages, TLT-1 deficiency accelerates fatty streak formation. After 20 weeks on HFD, lesions in both apoE - /- and [DN] mice progressed to an advance fibrous plaque stage. Although their lesion sizes were not substantially different, lesion compositions were. The mechanistic basis of these differences appears to be that the [DN] mice have significantly higher cholesterol levels when compared to apoE - /- mice. The increased cholesterol levels extend to the treml1 -/- mouse when compared to wild type mice at 4 weeks on HFD, this difference, however, gradually subsides as wild type mice cholesterol levels increase over 20 weeks. Interestingly, cholesterol levels in 50 week old mice on chow diet revealed minimal differences between test and control mice suggesting the higher cholesterol levels are related to increased dietary intake. Our work defines a surprising role for TLT-1 in the regulation of serum cholesterol levels during atherogenesis.

Abstract 156: Macrophage Low-Density Receptor--Related Protein 1 Deficiency Facilitates Atherosclerosis Regression in Hyperlipidemic Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Lin Zhu ◽  
Patricia G Yancey ◽  
Lei Ding ◽  
John L Blakemore ◽  
Youmin Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
Chow Diet ◽  
Low Density ◽  
Related Protein ◽  
Wild Type ◽  
Lesion Area ◽  
Cholesterol Levels ◽  
Inflammatory Macrophages

Atherosclerosis regression is characterized by egress of macrophages out of the artery wall. We have previously shown that macrophages lacking low-density receptor related protein 1 (MFLRP1-/-) are pro-inflammatory and lead to increased lesion formation in apoE-/- mice. To study the role of macrophage inflammation during atherosclerosis regression, bone marrow from four different types of mice (wild-type, MFLRP1-/-, apoE-/- and apoE-/-/ MFLRP1-/-) was transplanted into apoE-/- recipient mice who had been fed a Western-type diet for 12 weeks. ApoE-/- recipient mice transplanted with apoE-/- bone marrow were sacrificed 2 weeks post-BMT for determination of baseline aortic atherosclerosis. After 8 weeks on chow diet, cholesterol levels were normalized in mice reconstituted with wild-type (WT) and MFLRP1-/- bone marrow (157± 36 mg/dl and 136 ± 33 mg/dl, respectively), and significantly lowered in mice with apoE-/- (302±33 mg/dl) or apoE-/-/ MFLRP1-/- (294±52 mg/dl) macrophages compared to baseline (387±34 mg/dl). Total atherosclerotic lesion area in the aortic root decreased by 15% in mice receiving WT macrophages, and decreased by an additional 10% in mice transplanted with LRP1 deficient macrophages (p<0.05 compared to WT). Similarly, mice reconstituted with apoE-/-/ MFLRP1-/- bone marrow had 15% (p < 0.01) smaller lesion size than mice receiving apoE-/- marrow. The lesion area positive for CD68 was significantly smaller in MFLRP1-/- mice compared to WT mice, and in apoE-/-/ MFLRP1-/- mice compared to apoE-/- mice. The ratio of necrotic to total lesion area was significantly lowered by WT and LRP1-/- macrophages, and was also reduced in recipients of apoE-/-/MFLRP1-/- compared to apoE-/- bone marrow. Here we demonstrate that absence of LRP1 in macrophages, which is known to cause pro-inflammatory changes, promotes atherosclerosis regression. Our study supports the novel idea that pro-inflammatory macrophages efficiently egress from the plaque in a regressive environment caused by switching from a high-fat to a chow diet. This observation sets the stage for a change in paradigm on how to target inflammation for prevention of atherosclerotic cardiovascular events.

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 Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives

2018 ◽  
Vol 19 (11) ◽  
pp. 3512 ◽  
Author(s):  
Jianglin Fan ◽  
Yajie Chen ◽  
Haizhao Yan ◽  
Baoning Liu ◽  
Yanli Wang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Chow Diet ◽  
Low Density ◽  
Elevated Plasma ◽  
Wild Type ◽  
Very Low Density Lipoproteins

Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol-rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called β-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol.

scholarly journals Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Johanna P. van Geffen ◽  
Frauke Swieringa ◽  
Kim van Kuijk ◽  
Bibian M. E. Tullemans ◽  
Fiorella A. Solari ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
Thrombus Formation ◽  
Plasma Cholesterol ◽  
Chow Diet ◽  
Wild Type ◽  
Fibrin Formation ◽  
Established Risk Factor ◽  
Arterial Thrombus ◽  
Normal Chow ◽  
Platelet Proteome

AbstractHyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe−/− and Ldlr−/− mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe−/− mice). Bone marrow from wild-type or Ldlr−/− mice was transplanted into irradiated Ldlr−/− recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe−/− and Ldlr−/− mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.

EFFECTS OF AMPHENONE B AND OF DIET ON CHOLESTEROL LEVELS IN THE RAT

1959 ◽  
Vol 37 (1) ◽  
pp. 1069-1074 ◽  
Author(s):  
K. K. Carroll
Keyword(s):  
Erucic Acid ◽  
Plasma Cholesterol ◽  
Young Male ◽  
Cholesterol Content ◽  
Male Rats ◽  
Adrenal Weight ◽  
Chow Diet ◽  
Cholesterol Levels ◽  
High Doses

Amphenone B was added in concentrations of 0.1 to 0.5% to a number of synthetic diets and to a fox chow diet. These were then fed to young male rats to determine the effects on adrenal weight and on the cholesterol content of the adrenals, liver, and plasma. The rats fed amphenone mixed with synthetic diets showed a greater increase in adrenal size and adrenal cholesterol than those fed amphenone mixed with the chow diet. The liver and plasma cholesterol values of rats fed amphenone on synthetic diets were also increased appreciably while those of rats fed amphenone in the chow diet were near normal. Synthetic diets containing erucic acid and amphenone appeared to have the greatest effect on adrenal size and cholesterol content but other synthetic diets in some cases caused a greater increase in liver and plasma cholesterol concentrations. An attempt to examine the effect of injected amphenone on cholesterol levels in rats fed different diets was limited by the fact that high doses of amphenone cause prolonged anesthesia.

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.

scholarly journals A comparison of the effects of soya-bean protein and casein on bile composition, cholelithiasis and serum lipoprotein lipids in the vervet monkey (Cercopithecus aethiops)

1987 ◽  
Vol 58 (2) ◽  
pp. 257-263 ◽  
Author(s):  
K. Jaskiewicz ◽  
M. J. Weight ◽  
K. J. Christopher ◽  
A. J. S. Benadé ◽  
D. Kritchevsky
Keyword(s):  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Soya Bean ◽  
Protein Source ◽  
Vervet Monkeys ◽  
Biopsy Material ◽  
Bile Composition ◽  
Cholesterol Levels ◽  
Significant Difference ◽  
Bean Protein

1. Two groups of vervet monkeys (Cercopithecus uethiops) were fed on high-cholesterol diets which differed only with respect to the protein source. In one group casein was the only protein source, while the other group received only soya-bean protein.2. Samples of blood, bile and liver biopsy material were collected at the commencement of the study and at 3-monthly intervals until termination 12 months later.3. At the end of the experimental period all the animals (n19) had high plasma cholesterol levels and had developed pigment gallstones, the compositions and weights of which were not related to the protein source or to plasma cholesterol levels. Gallstone weight was related to the presence of acidic and sulphated mucins in gallbladder mucosa. We were also unable to confirm the hypocholesterolaemic effect of soya-bean protein which has been demonstrated previously in rhesus monkeys and hamsters. Bile composition, and plasma lipids did not differ significantly between the casein-fed and soya-bean fed animals. Lithogenic index was below 1 for both groups and did not differ significantly between the two groups.4. No significant difference was found in the severity ofcholelithiasis between the casein-fed and the soya-bean-fed animals.

Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia

2011 ◽  
Vol 301 (4) ◽  
pp. H1405-H1414 ◽  
Author(s):  
Michelle L. Bullen ◽  
Alyson A. Miller ◽  
Janahan Dharmarajah ◽  
Grant R. Drummond ◽  
Christopher G. Sobey ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Soluble Guanylyl Cyclase ◽  
Vascular Diseases ◽  
Normal Diet ◽  
Wild Type ◽  
Novel Treatments ◽  
Cholesterol Levels ◽  
Deficient Mice

Nitroxyl (HNO) displays pharmacological and therapeutic actions distinct from those of its redox sibling nitric oxide (NO∙). It remains unclear, however, whether the vasoprotective actions of HNO are preserved in disease. The ability of the HNO donor isopropylamine NONOate (IPA/NO) to induce vasorelaxation, its susceptibility to tolerance development, and antiaggregatory actions were compared with those of a clinically used NO∙ donor, glyceryl trinitrate (GTN), in hypercholesterolemic mice. The vasorelaxant and antiaggregatory properties of IPA/NO and GTN were examined in isolated carotid arteries and washed platelets, respectively, from male C57BL/6J mice [wild-type (WT)] maintained on either a normal diet (WT-ND) or high fat diet (WT-HFD; 7 wk) as well as apolipoprotein E-deficient mice maintained on a HFD (ApoE−/−-HFD; 7 wk). In WT-ND mice, IPA/NO (0.1–30 μmol/l) induced concentration-dependent vasorelaxation and inhibition of collagen (30 μg/ml)-stimulated platelet aggregation, which was predominantly soluble guanylyl cyclase/cGMP dependent. Compared with WT-HFD mice, ApoE−/−-HFD mice displayed an increase in total plasma cholesterol levels ( P < 0.001), vascular ( P < 0.05) and platelet ( P < 0.05) superoxide (O2·−) production, and reduced endogenous NO∙ bioavailability ( P < 0.001). Vasorelaxant responses to both IPA/NO and GTN were preserved in hypercholesterolemia, whereas vascular tolerance developed to GTN ( P < 0.001) but not to IPA/NO. The ability of IPA/NO (3 μmol/l) to inhibit platelet aggregation was preserved in hypercholesterolemia, whereas the actions of GTN (100 μmol/l) were abolished. In conclusion, the vasoprotective effects of IPA/NO were maintained in hypercholesterolemia and, thus, HNO donors may represent future novel treatments for vascular diseases.

EFFECTS OF AMPHENONE B AND OF DIET ON CHOLESTEROL LEVELS IN THE RAT

1959 ◽  
Vol 37 (9) ◽  
pp. 1069-1074
Author(s):  
K. K. Carroll
Keyword(s):  
Erucic Acid ◽  
Plasma Cholesterol ◽  
Young Male ◽  
Cholesterol Content ◽  
Male Rats ◽  
Adrenal Weight ◽  
Chow Diet ◽  
Cholesterol Levels ◽  
High Doses

Amphenone B was added in concentrations of 0.1 to 0.5% to a number of synthetic diets and to a fox chow diet. These were then fed to young male rats to determine the effects on adrenal weight and on the cholesterol content of the adrenals, liver, and plasma. The rats fed amphenone mixed with synthetic diets showed a greater increase in adrenal size and adrenal cholesterol than those fed amphenone mixed with the chow diet. The liver and plasma cholesterol values of rats fed amphenone on synthetic diets were also increased appreciably while those of rats fed amphenone in the chow diet were near normal. Synthetic diets containing erucic acid and amphenone appeared to have the greatest effect on adrenal size and cholesterol content but other synthetic diets in some cases caused a greater increase in liver and plasma cholesterol concentrations. An attempt to examine the effect of injected amphenone on cholesterol levels in rats fed different diets was limited by the fact that high doses of amphenone cause prolonged anesthesia.

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