193 apo b48 secretion and regulation
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The document presents research on the secretion and regulation of apolipoprotein B48 (ApoB48) by primary hamster intestinal enterocytes. Studies show increased intracellular stability and oversecretion of ApoB48 from fructose-fed hamster enterocytes. The results suggest that hyperinsulinemia and increased de novo lipogenesis in the intestine may enhance ApoB48 secretion and contribute to elevated triglyceride levels.
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I. The document discusses studies on the effects of oral administration of apolipoprotein A-I mimetic peptides synthesized from D-amino acids in reducing atherosclerosis in mice. It was found to dramatically decrease lesions by 75-79% independent of changes in total or HDL cholesterol.
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I. This document discusses various animal models that have been used to study atherosclerosis and plaque rupture, including quail, pigeons, chickens, dogs, monkeys, pigs, rats, rabbits, and mice. It provides details on the types of lesions developed and similarities to human disease for each model.
II. The double knockout LDL/apoE mice are highlighted as offering improvements in studying clinical complications of atherosclerosis like human heart disease. However, it is unclear how closely they model vulnerable plaques.
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II. Studies have shown several MMPs (MMP-1, -2, -3, -9, -12) present in atherosclerotic plaques and implicated in plaque development and rupture. MMP-8 was also found to be associated with collagen degradation in plaque shoulders, a site of rupture.
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042 introducing a novel model
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II. The peptide is proposed to be useful for preventing and treating atherosclerosis and other inflammatory diseases caused by oxidized lipids. Its ability to reduce lesions orally suggests potential as a therapeutic agent.
III. Further studies are referenced that examine the mechanisms of action of apo A-I and analogs in protecting against atherosclerosis through reverse cholesterol transport and removal of oxidized lipids.
225 animal models of heart attack part 2
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II. The double knockout LDL/apoE mice are highlighted as offering improvements in studying clinical complications of atherosclerosis like human heart disease. However, it is unclear how closely they model vulnerable plaques.
III. Questions are raised about how closely the coagulation systems of these animal models resemble humans and whether any model fully captures repeated plaque ruptures and the role of aging in natural history as seen in humans.
120 mr imaging for the evaluation of carotid atherosclerosis
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1. This study aims to identify genomic and proteomic risk factors and protective factors associated with coronary heart disease by analyzing gene and protein expression profiles in blood cells from patients with and without heart disease.
2. The study will recruit patients aged 18-80 categorized into five groups based on having heart disease and traditional risk factors. Gene expression in monocytes and neutrophils will be analyzed using microarray technology and real-time PCR.
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098 red wine and heart disease
1) The study found that red wines from France increased expression of the endothelial nitric oxide synthase (eNOS) gene and protein in human endothelial cells, whereas red wines from Germany did not.
2) French red wines were also found to increase activity of the eNOS promoter and stability of eNOS mRNA, resulting in increased production of bioactive nitric oxide (NO) from the endothelial cells.
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039 mr contrast agents for vulnerable plaque imaging
1. MS-325 is an albumin-targeted gadolinium contrast agent that highlights inflamed vessel walls and facilitates plaque imaging. It provides prolonged enhancement of the vessel wall and lumen, allowing for high resolution detection of plaque burden.
2. Studies show strong vessel wall enhancement with MS-325 due to increased capillary volume and binding to extravasated albumin in the vessel wall of patients with atherosclerosis. This may help identify stenosis and quantify plaque.
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091 vascular dysfunction in hypercholesterolemic rabbits
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502 nmr relaxation times
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2. Preliminary studies in rabbits and humans also showed greater SPIO uptake and more CD68+ cells in periadventitial fat of diseased vessels compared to normal vessels.
3. The cells in periadventitial fat are not dendritic cells, mast cells, or adipocytes, and show some similarities to stromal vascular fraction cells. Their role in atherosclerosis progression requires further investigation.
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This study found that temperature heterogeneity in atherosclerotic plaques in rabbits is associated with macrophage accumulation and metalloproteinase (MMP) activity. Thermography detected hot and cold areas that correlated with higher macrophage levels and MMP-2 and MMP-9 activity. More macrophages and MMPs were present in hot areas compared to cold areas of plaques. However, blood flow obscured temperature differences, so flow was stopped to measure temperatures accurately. The results suggest temperature changes detect active macrophages and areas of plaques with higher vulnerability.
058 optical coherence tomography
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This document summarizes research on using optical coherence tomography (OCT) to characterize coronary plaques. OCT uses near-infrared light to generate high-resolution cross-sectional images of tissue microstructure. Researchers studied 357 arterial segments ex vivo using OCT and validated plaque types (fibrous, calcific, lipid-rich) against histology with high accuracy. A pilot clinical study of 10 patients found OCT feasible and safe for in vivo coronary imaging before and after percutaneous coronary intervention, identifying a variety of plaque types and stent appositions. While blood obstruction and motion artifacts posed challenges, the results support further evaluation of OCT as a potential "optical biopsy" tool.
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This document discusses inflammation in coronary arteries and culprit lesions. It finds that:
1. Inflammation is present in many non-culprit lesions, not just culprit lesions, based on a study of 74 coronary arteries.
2. Inflammation therefore has a very low positive predictive value (<3%) for identifying the actual culprit lesion responsible for a clinical event like a heart attack.
3. Inflammation appears to be a local arterial phenomenon, as cross-sectional sampling of inflammation in one part of an artery did not strongly correlate with levels in other parts or in paired left/right arteries.
140 mr imaging of fibrin
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071 carotid array coil
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254 nanotechnology
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154 plaque rupture definition
The document defines plaque rupture as the structural failure of the fibrocellular cap separating an atheromatous core from the lumen of an atherosclerotic artery. It then discusses factors that increase the propensity of plaque rupture like a lipid-rich core and lack of a fibrous cap. Several studies are summarized that show plaque rupture is the cause of fatal thrombosis in 75-100% of cases of acute MI and sudden cardiac death when examined post-mortem. The role of traditional risk factors like age, sex, cholesterol levels, and smoking in rupture vs. non-rupture cases is then assessed based on multiple studies.
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This document provides background on Jacques Barth, an expert in cardiovascular imaging and risk assessment. It discusses the evolution of ultrasound technology for measuring intima-media thickness (IMT) from 1986 to 2005. IMT is an early marker of atherosclerosis and cardiovascular risk. The document also addresses issues around vulnerable plaques, reporting IMT measurements, and assessing cardiovascular risk in children and adolescents.
Braunwald
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176 coronary pan artritis
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1) Inflammation is common in deeper layers of atherosclerotic plaques and is associated with lipid content but not necessarily plaque rupture.
2) Patients with unstable angina tend to have evidence of widespread coronary inflammation, not just at the culprit lesion, suggesting vulnerable plaques may form throughout the arteries.
3) Given that vulnerable patients often have many inflamed plaques, targeting a single coated stent to one region may not be sufficient as a treatment approach for reducing acute coronary events risk.
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The document describes results from experiments studying iron uptake and macrophage presence in the periaortic and pericoronary fat of mice, rabbits, and humans with atherosclerosis. Mice and rabbits genetically modified to be prone to atherosclerosis showed greater iron uptake and more macrophages in the periaortic fat compared to controls. In humans, macrophages were found not just in atherosclerotic plaques but also in the surrounding pericoronary fat tissue.
Acc presentation lipid coated(2)
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259 crp as a risk factor
This document discusses the use of C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol levels to predict cardiovascular risk. It summarizes a study that found CRP to be a stronger predictor of future cardiovascular events than LDL. The study measured CRP and LDL levels in 27,939 healthy women and followed them for 8 years, finding that most cardiovascular events occurred in women with normal or low LDL (<160 mg/dl) but elevated CRP. The document concludes that combining CRP and LDL measurements provides better risk assessment than either marker alone.
220 statin therapy and coronary calcification
This study investigated whether statin therapy can slow or reverse coronary calcification in hyperlipidemic patients. 72 patients underwent electron beam tomography scans at years 1 and 2: the first year with no lipid treatment, the second year taking cerivastatin. Cerivastatin significantly reduced LDL cholesterol and slowed the progression of coronary calcification, demonstrating an 8.8% increase in calcium volume score from years 1 to 2 compared to a 25% increase with no treatment. While reversal was not shown for the whole group, patients achieving an LDL <100 mg/dl had a slightly negative calcium change. This provides further evidence that statins can slow atherosclerotic progression.
200 is coated stent the answer
This document discusses drug-coated stents for preventing restenosis. It summarizes a study showing that stents coated with the immunosuppressant sirolimus reduced restenosis by 50% by inhibiting cell proliferation. While adding dexamethasone provided no additional benefit. If further trials confirm the results, sirolimus-coated stents may become the standard therapy for coronary revascularization. However, questions remain about whether coating and stenting all vulnerable plaques found is the best long-term treatment approach.
091 vascular dysfunction in hypercholesterolemic rabbits
This study investigated the effects of exercise training on vascular dysfunction in hypercholesterolemic rabbits. Rabbits were fed either a normal or high-cholesterol diet, with some receiving exercise training. The high-cholesterol diet led to increased lipid deposition, impaired vasorelaxation, and elevated inflammatory markers in the aortas. However, exercise training reduced lipid deposition, improved vasorelaxation, and decreased inflammatory marker expression in the high-cholesterol diet rabbits. The results suggest that exercise training can ameliorate vascular damage caused by hypercholesterolemia.
502 nmr relaxation times
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050 periadventitial fat
1. The study found that periadventitial fat tissue in atherosclerotic mouse models takes up more of the MRI contrast agent SPIO than normal mice, and contains more macrophage-like cells.
2. Preliminary studies in rabbits and humans also showed greater SPIO uptake and more CD68+ cells in periadventitial fat of diseased vessels compared to normal vessels.
3. The cells in periadventitial fat are not dendritic cells, mast cells, or adipocytes, and show some similarities to stromal vascular fraction cells. Their role in atherosclerosis progression requires further investigation.
4th vulnerable plaque symposium
This study found that temperature heterogeneity in atherosclerotic plaques in rabbits is associated with macrophage accumulation and metalloproteinase (MMP) activity. Thermography detected hot and cold areas that correlated with higher macrophage levels and MMP-2 and MMP-9 activity. More macrophages and MMPs were present in hot areas compared to cold areas of plaques. However, blood flow obscured temperature differences, so flow was stopped to measure temperatures accurately. The results suggest temperature changes detect active macrophages and areas of plaques with higher vulnerability.
058 optical coherence tomography
This document summarizes research on using optical coherence tomography (OCT) to characterize coronary plaques. OCT uses near-infrared light to generate high-resolution cross-sectional images of tissue microstructure. Researchers studied 357 arterial segments ex vivo using OCT and validated plaque types (fibrous, calcific, lipid-rich) against histology with high accuracy. A pilot clinical study of 10 patients found OCT feasible and safe for pre- and post-percutaneous coronary intervention imaging, identifying a variety of plaque types and stent placements. While blood obstruction and motion artifacts posed challenges, the results support further evaluation of OCT as a potential "optical biopsy" tool.
3rd vp symposium jang
This document summarizes research on using optical coherence tomography (OCT) to characterize coronary plaques. OCT uses near-infrared light to generate high-resolution cross-sectional images of tissue microstructure. Researchers studied 357 arterial segments ex vivo using OCT and validated plaque types (fibrous, calcific, lipid-rich) against histology with high accuracy. A pilot clinical study of 10 patients found OCT feasible and safe for in vivo coronary imaging before and after percutaneous coronary intervention, identifying a variety of plaque types and stent appositions. While blood obstruction and motion artifacts posed challenges, the results support further evaluation of OCT as a potential "optical biopsy" tool.
129 inflammation and culprit lesions
This document discusses inflammation in coronary arteries and culprit lesions. It finds that:
1. Inflammation is present in many non-culprit lesions, not just culprit lesions, based on a study of 74 coronary arteries.
2. Inflammation therefore has a very low positive predictive value (<3%) for identifying the actual culprit lesion responsible for a clinical event like a heart attack.
3. Inflammation appears to be a local arterial phenomenon, as cross-sectional sampling of inflammation in one part of an artery did not strongly correlate with levels in other parts or in paired left/right arteries.
140 mr imaging of fibrin
The document discusses research into using MRI with fibrin-targeted gadolinium contrast agents to detect vulnerable plaques associated with heart attacks, presenting findings that this approach can successfully identify fibrin deposits in thrombi in animal studies and has potential for sensitive detection of injured plaques in humans; it also notes the need for more studies to develop highly sensitive targeted contrast agents for multiple imaging modalities to identify vulnerable plaque features beyond structure.
Acc presentation macrophage (1)
This document proposes a non-invasive method using SPIO (super paramagnetic iron oxide) nanoparticles to image macrophage infiltration and inflammation in vulnerable atherosclerotic plaques. Rabbits and mice were injected with SPIO, which accumulated in inflamed plaque areas correlated with macrophage density. SPIO-enhanced MRI then successfully identified these inflamed plaques non-invasively in vivo. This technique could provide a way to detect rupture-prone plaques and better understand plaque vulnerability.
071 carotid array coil
The document describes the Pathway MRITM Carotid Array coil, which is designed for high resolution imaging of small soft tissue structures like the carotid arteries. It provides images showing atherosclerotic plaque buildup in the carotid arteries, including plaque in the common carotid artery, carotid bifurcation, and internal carotid artery stenosis and plaque.
254 nanotechnology
- Nanotechnology shows promise for combining molecular imaging and targeted drug delivery for vulnerable plaques. Molecular imaging aims to enhance detection of pathologies by targeting disease biomarkers. MRI and CT are imaging modalities that could track molecular phenomena using nanoparticle contrast agents. ICAM-1 is proposed as an attractive target for delivering anti-thrombotic and anti-inflammatory drugs to vascular beds due to its expression on endothelial lumens. Future in vivo studies are needed to evaluate this new therapeutic approach of targeting ICAM-1.
165 pressure wire
This document reports on a study that used a pressure wire to measure intracoronary temperatures in patients referred for cardiac catheterization. Temperature mappings were recorded in various coronary arteries. Measurements were taken in patients presenting with conditions such as unstable angina, stable angina, prior myocardial infarction, and no cardiac symptoms. The data collected included temperature, location of any stenotic lesions, and patient demographics and risk factors. Statistical analyses were also performed on the temperature readings.
154 plaque rupture definition
The document defines plaque rupture as the structural failure of the fibrocellular cap separating an atheromatous core from the lumen of an atherosclerotic artery. It then discusses factors that increase the propensity of plaque rupture like a lipid-rich core and lack of a fibrous cap. Several studies are summarized that show plaque rupture is the cause of fatal thrombosis in 75-100% of cases of acute MI and sudden cardiac death when examined post-mortem. The role of traditional risk factors like age, sex, cholesterol levels, and smoking in rupture vs. non-rupture cases is then assessed based on multiple studies.
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This document discusses the use of coronary CT angiography (CTA) to detect and characterize coronary atherosclerosis beyond just detecting coronary stenoses. CTA can identify calcified plaques, non-calcified plaques, and mixed plaques. It can detect atheromas and characterize plaque density. CTA can also identify intracoronary thrombi and myocardial infarction scars. The document outlines the CTA scanning parameters and techniques used to minimize motion artifacts and optimize image quality for plaque detection and characterization.
Acc presentation (1)
This document describes a study that introduces a non-invasive method for imaging macrophage infiltration in inflamed atherosclerotic plaques using superparamagnetic iron oxide (SPIO) nanoparticles and MRI. The researchers injected SPIO into hypercholesterolemic and normal rabbits and found that SPIO profoundly accumulated in areas of macrophage infiltration in the atherosclerotic plaques, as confirmed by histology. SPIO-enhanced MRI was able to identify these inflamed plaques non-invasively. The results suggest SPIO-enhanced MRI can be a novel method for detecting rupture-prone inflamed plaques associated with heart attacks and strokes.
Ac cculprit
The document discusses several factors that are considered predictors of plaque vulnerability, including luminal narrowing, plaque volume and composition, fibrous cap thickness, and plaque inflammation. It reviews studies that show myocardial infarction can develop from previously non-severe lesions and that lipid content, cap thickness, inflammation, and stress factors like circumferential stress are correlated with plaque stability and vulnerability. In conclusion, the size and composition of the lipid core, thickness and composition of the fibrous cap, and inflammation are well-established predictors of plaque rupture.
Acc 2002 microarray mehran for print
This document discusses the use of DNA microarrays in vulnerable plaque research. It provides background on atherosclerosis and identifies DNA microarrays as a tool that can be used to investigate the molecular mechanisms underlying plaque vulnerability. The document outlines the basic steps of a DNA microarray experiment and discusses considerations for experimental design, data analysis, and validation of results. It also summarizes several studies that have used DNA microarrays or related techniques to examine gene expression in atherosclerosis.
Acc booth inventory
The document provides details about AEHA's booth at the ACC/AEHA Exhibition from March 30 to April 1, 2003. It lists the booth equipment and inventory, proposed activities like an Ecode on Friday morning and a VP Symposium. Giveaways include Magellan GPS devices in a raffle and Dove chocolates. It also discusses the need for an immediate membership sign-up page on the AEHA website and a vision for the future of AEHA.
Acc 04 vuln pt
This document discusses approaches to identifying and managing coronary risk. It states that the primary goal should be preventing acute cardiac events through intensive risk factor reduction for all patients with clinically apparent heart disease. Additionally, it notes that one third of sudden cardiac deaths and heart attacks occur in previously asymptomatic individuals with undiagnosed risk factors or pre-clinical disease. The document proposes identifying high-risk asymptomatic individuals through testing to provide prevention. It presents a risk stratification approach using testing like CRP, cholesterol, glucose and imaging to guide different levels of risk factor reduction and management.
Acc 2002 mehran for print
This document discusses the use of DNA microarrays in studying vulnerable atherosclerotic plaques. It provides background on atherosclerosis and plaque rupture. DNA microarrays allow high-throughput analysis of gene and protein expression, which can provide insights into molecular mechanisms underlying plaque vulnerability. One study used microarrays to analyze gene expression differences between ruptured and stable plaques, identifying perilipin as upregulated in ruptured plaques. However, microarray analysis of atherosclerosis is still in its early stages with many technical challenges to address.
Acc2002 thermography
Vulnerable plaques are prone to rupture and cause heart attacks. This document proposes criteria for defining vulnerable plaques based on histopathology and clinical factors. It also explores using infrared thermography to identify vulnerable plaques by detecting heat from macrophage inflammation. Studies in animal models and humans found temperature heterogeneity in atherosclerotic arteries that correlated with plaque vulnerability features. Further research aims to develop non-invasive thermography techniques to accurately detect vulnerable plaques and help predict heart attack risk.
A20 gene
The document presents findings on the A20 gene, which encodes a zinc finger protein that inhibits NF-kB activity and TNF-induced apoptosis. The study found that C57 and FVB mouse strains have a coding difference in A20 that generates a phosphorylation site in C57 mice. C57-A20 was less effective at shutting down TNF-induced NF-kB activity and C57 cells were less susceptible to TNF-induced apoptosis compared to FVB cells. This suggests less active A20 in C57 mice leads to increased inflammation and reduced apoptosis, while more active A20 in FVB mice decreases inflammation and increases apoptosis, contributing to differences in atherosclerosis susceptibility between the strains.
#1 killer of human beings in the 21st century
Vulnerable plaque refers to dangerous forms of atherosclerotic plaques that can rupture or induce thrombosis, disrupting blood flow. The document discusses the history and research around vulnerable plaque, including pioneers in the field and emerging techniques to detect vulnerable plaque such as intravascular ultrasound, optical coherence tomography, and magnetic resonance imaging. It summarizes that vulnerable plaques are typically characterized by a thin fibrous cap, large lipid core, and presence of macrophages.
A20 is an atherosclerosis
The document presents findings on the A20 gene, which encodes a zinc finger protein that inhibits NF-kB activity and TNF-induced apoptosis. The study found that C57 and FVB mouse strains have a coding difference in A20 that generates a putative phosphorylation site in C57 mice. Experiments showed the C57 version of A20 is less effective at shutting down NF-kB activity and C57 cells are less susceptible to TNF-induced apoptosis. This suggests the A20 variation could contribute to differences in atherosclerosis susceptibility between C57 and FVB strains by affecting inflammation and apoptosis.
103100
This progress report discusses ongoing near-infrared (NIR) spectroscopy studies. It notes that a new probe design is being developed to improve signal detection in the NIR range. Characterization of a new light source and additional tissue phantom studies are needed. The report identifies ongoing difficulties with depth penetration studies and experimental setup issues. Priorities include analyzing existing data to inform probe redesign, characterizing the new light source, conducting depth penetration and tissue phantom studies, and addressing experimental setup challenges.
511 first steps towards understanding
This study investigated genetic differences in vascular remodeling and shear stress regulation in response to altered blood flow in four inbred rat strains. The results showed significant differences among strains in their ability to maintain normal endothelial shear stress levels through outward arterial remodeling when flow was increased or decreased. Specifically, the GH strain was better able to regulate shear stress through remodeling compared to the SHR-SP strain. These genetic differences in vascular responses to changes in blood flow have important implications for understanding the variable manifestations of atherosclerosis and susceptibility to cardiovascular disease in individuals and populations. Future studies are needed to investigate whether similar genetic differences exist in humans and their role in clinical outcomes.
1688 azadpour 3 12 02
This document contains fluorescence intensity measurements from a fluorescence-based assay using different concentrations of FITC-labeled superparamagnetic iron oxide nanoparticles (FITC SPIO). The measurements are organized in a table with concentrations of FITC SPIO along the left and average fluorescence units per well and standard deviations for different samples labeled with letters in the cells.
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193 apo b48 secretion and regulation
- 1. Secretion and Regulation of ApoB48 by Primary Hamster Intestinal EnterocytesIntestinal Enterocytes B C LabeledApoB48(%control) LabeledApoB48(%control) 0 20 40 60 80 100 120 Total Cells Media Control MG132 P < 0.05 0 20 40 60 80 100 120 Total Cells Media Control Oleate P = 0.01 Cells Media 0 45 90 45 90 A Chase Time (min)
- 2. Cells Media Fructose-Fed Chow-Fed Chase Time (Min) 0 45 90 45 90 D Chase Time (Min) Chase Time (Min) 100 100 0 10 20 30 40 50 60 70 80 90 0 20 40 60 80 Total apoB 48 LabeledApoB48(%of0Time) LabeledApoB48(%of0Time) p= 0.003 p= 0.001 Secreted apoB 48 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 Chow-Fed Fructose-Fed E F Ex vivo evidence for oversecretion of intestinal apoB48 & Enhanced intracellular apoB48 stability in fructose- fed hamster enterocytes
- 3. In Vivo Production of TG & Intestinal ApoB48 in the Fasting State Time (min) 55 60 65 70 75 80 85 Sf>400TGconcentration (mmol/l) 0 1 2 3 4 Sf >400 after Triton WR1339 Time (min) 55 60 65 70 75 80 85 Sf>400ApoB48concentration (µg/ml) 140 160 180 200 220 240 260 280 Time (min) 55 60 65 70 75 80 85 Sf100-400TGconcentration (mmol/l) 0 1 2 3 Sf 100-400 after Triton WR1339 Time (min) 55 60 65 70 75 80 85 Sf100-400ApoB48concentration (µg/ml) 90 100 110 120 130 140 150 160 170 Triglyceridesecretion 0.0 0.2 0.4 0.6 0 1 2 3 ApoB48secretion 0 4 8 12 16 Triglyceridesecretion 0.0 0.1 0.2 0.3 ApoB48secretion 0 2 4 6p = 0.002 p = 0.01 p = 0.14 p = 0.59 A B DC
- 4. In Vivo Production of TG & Intestinal ApoB48 in the Postprandial State Time (min) 55 60 65 70 75 80 85 Triglyceridelevel(mmol/l) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Time (min) 55 60 65 70 75 80 85 ApoB48level(µg/ml) 80 90 100 110 120 130 140 150 Time (min) 55 60 65 70 75 80 85 Triglyceridelevel(mmol/l) 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Time (min) 55 60 65 70 75 80 85 ApoB48level(µg/ml) 50 60 70 80 90 100 Triglyceridesecretion(µmol/min) 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Col 48: 0.07 Col 48: 0.06 Triglyceridesecretion(µmol/min) 0.00 0.02 0.04 0.06 0.08 0.10 Col 50: 0.08 Col 50: 0.09 0 1 2 3 ApoB48secretion(µg/min) 0 1 2 3 4 5 6 7 8 Col 52: 2.65 Col 52: 7.46 ApoB48secretion(µg/min) 0 1 2 3 4 5 6 7 8 Col 54: 3.85 Col 54: 7.26 Sf 100-400 after Triton WR1339 Sf >400 after Triton WR1339 A B C D p = 0.3 p = 0.003 p = 0.8 p = 0.007
- 5. 0 20 40 60 80 100 120 140 160 Fructose-Fed MTPProteinMass (%ofControl) Chow-Fed Fructose-Fed 0 20 40 60 80 100 120 0 0.5 1 1.5 2 2.5 3 3.5 MTP inhibitor (µM) ApoB48Secretion(%ofcontrol) Fructose-fed Chow-fed ∗ ∗ ∗ ∗ Chow-Fed p=0.006D E LabeledCholesterylEster (%ofControl) p= 0.002 0 50 100 150 200 250 Cellular p=0.001 Media B LabeledCholesterol (%ofControl) Chow-Fed Fructose-Fed 0 100 200 300 400 500 600 700 800 Cellular p=0.0018 p=0.0013A Media LabeledTriglyceride (%ofControl) Cellular 0 20 40 60 80 100 120 140 160 180 p=0.04 p=0.003 Media C Ex Vivo Evidence for Intestinal Overproduction of Lipoprotein Lipids and Increase MTP mass/activity
- 6. Fructose-Fed Chow-fed 0 10 20 30 40 50 60 70 80 Large CM Small CM VLDL LDL HDL p<0.05 p= 0.06 p<0.03 %ofTotalLabeledApoB48 A 0 20 40 60 80 100 120 140 CM apoB48 Total-apoB48 LabeledApoB48 (%ofFructose-fed) p<0.0007 p<0.01C 0 10 20 30 40 50 60 70 80 Particles< 1.006 Particles > 1.006 %ofTotalLabeledAPoB48 p<0.024 p<0.026 B 0 40 20 60 80 100 120 CM apoB48 Total apoB48 LabeledApoB48 (%ofFructose-fed) P=0.008 P=0.0001 DFasting Postprandial Density/Size Distribution of Intestinal Lipoproteins Evidence for Increased Number & Size
- 7. Increased De Novo Lipogenesis in FF Enterocytes Evidence that ApoB48 Secretion is Linked to the Rate of De Novo Lipogenesis 0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 Cholesterol Fatty Acid Triglyceride LabeledLipid(%ascontrol) Cerulenin µg/ml 0 50 100 150 200 250 300 350 Chow-fed Fructose-fed LabeledFattyAcid(%ascontrol) 0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 Cerulenin µg/ml LabeledSecretedApoB-48(%ascontrol) A C p= 0.002 Sensitivity of ApoB48 Secretion to Cerulenin Fatty Acid Synthesis Sensitivity of TG & FA Secretion to Cerulenin
- 8. 20 60 80 100 0 40 120 Chow-fed Fructose-fed (2 days) 0 20 40 60 80 100 120 Control Fructose (3mM ) 0 200 400 600 800 1000 enterocytes hepatocytes P < 0.01 LabeledApoB-48(%ofcontrol) LabeledApoB-48(%ofcontrol) Labeledcholesterol 0 50 100 150 200 250 300 350 400 450 enterocytes hepatocytes LabeledTriglyceride P < 0.0001 Acute Fructose Feeding or Exposure Does NOT Affect Intestinal ApoB48 Secretion [14 C] Fructose Incorporation into TG & Cholesterol Two-day Fructose Feeding In Vitro Incubation of Enterocytes with Fructose
- 9. Mechanisms of Intestinal Lipoprotein Overproduction in Insulin Resistant/ Hyperinsulinemic States Apical Surface Basolateral Surface FA monoglyceride FABP-FA FABP TG TG TG ApoB48 PL CE De Novo (FA) Insulin (??) TGdietary SOS Grb-2 IRS PI3-K p110 SHP-2 NCK PTKPTK β β α α IR PKB (Akt) SREBP1c FAS & ACC Glucose + FA MTP ERER GolgiGolgi Intestinal Enterocyte TG ApoB48 Lipoprotein Particles p85Proteasome Degradation
- 10. Acknowledgements Laboratory Group: Changiz Taghibiglou Mehran Haidari Steven Van Iderstine Wei Qui Taryne Chong Farhana Mahboob Biao Chen Leyla Mangaloglu Louisa Pontrelli Fariborz Rashid Rita Kohen Debbie Rudy Collaborators: Gary Lewis- Toronto Andre Carpentier- Sherbrooke Sven Olof Olofsson - Sweden Janet Sparks - Rochester, NY Raphael Cheung – Windsor Michel Tremblay – Montreal Denny Trinh - Toronto Funding: Heart & Stroke Foundation of Ontario Canadian Institutes of Health Research NSERC Hospital for Sick Children Merck-Frosst pfizer GlaxoSmithKline BBDC, University of Toronto