Papers by karpagam aravindhan
Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 1, 2010
Purpose-This study assessed the pharmacological effect of a novel selective CC chemokine receptor... more Purpose-This study assessed the pharmacological effect of a novel selective CC chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model. Methods and Results-Apolipoprotein E Ϫ/Ϫ mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (PϽ0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (PϽ0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (PϽ0.05). Conclusion-An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.
Circulation, Nov 11, 2003
Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is expressed in the heart and re... more Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-␣ in acute ischemia/reperfusion myocardial injury remains unclear. Methods and Results-The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-␣ agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg • kg Ϫ1 • d Ϫ1 reduced infarct size by 28% and 35%, respectively (PϽ0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-␣-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-␣ and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and-2. Furthermore, GW7647 inhibited nuclear factor-B activation in the heart, accompanied by enhanced levels of inhibitor-B␣. Conclusions-Activation of PPAR-␣ protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-␣ agonist could provide an added benefit to patients treated with PPAR-␣ activators for dyslipidemia. (Circulation. 2003;108:2393-2399.
Journal of the Endocrine Society, 2021
Increased fibroblast growth factor 23 (FGF23) levels are an independent predictor for adverse car... more Increased fibroblast growth factor 23 (FGF23) levels are an independent predictor for adverse cardiac events suggesting a role as a link that drives cardiomyopathic changes in cardiorenal syndrome. The search for the underlying mechanism driving this interaction has led to the hypothesis that FGF23 causes pathogenic changes in the heart. Increased serum FGF23 has been independently shown to cause increased cardiac morbidity, mortality, and hypertrophy by signalling through FGF receptor 4. This mechanistic concept was based on preclinical studies demonstrating inhibition of FGF23 signaling through FGF4, which led to suppression of left ventricular hypertrophy and fibrosis in a 2-week rat 5/6 nephrectomy study and a 12-week (2%) high-phosphate diet mouse model in which FGF23 levels were markedly elevated. In this report, renal dysfunction was observed in the 5/6 nephrectomy model, and FGF23 levels were significantly elevated, whereas no changes in left ventricular hypertrophy were obs...
Circulation, Oct 16, 2007
<jats:p> <jats:bold>Introduction</jats:bold> Abdominal aortic aneurysms (AAA) c... more <jats:p> <jats:bold>Introduction</jats:bold> Abdominal aortic aneurysms (AAA) can be consistently produced in hyperlipidimic mice by continuous infusion of Angiotensin-II (Ang-II). MRI allows for AAA visualization <jats:italic>in-vivo</jats:italic> with sufficient spatial resolution to assess changes in aneurysm size and morphology. Bright-blood contrast allows for detection of medial breaks, an index of AAA severity, and USPIO contrast agent uptake allows for detection of macrophage activity in AAA. For this study we used MRI to characterize AAA development in a murine model and examined the effect of the broad-based MMP inhibitor, doxycycline, on AAA progression over a 4 week period. </jats:p> <jats:p> <jats:bold>Methods</jats:bold> Osmotic pumps were implanted subcutaneously in ApoE−/− mice for infusion of Ang-II (1000 ng/kg/min) over 4 weeks. Animals were given 30 mg/kg/day doxycycline or vehicle (n=15 per group) via drinking water. Weekly scans were performed using a 9.4T MRI scanner. In addition, uptake of USPIO (Combidex, 1000 μmol/kg) in AAA was measured. </jats:p> <jats:p> <jats:bold>Results</jats:bold> MRI revealed two distinct features of AAA development: remodeling of the adventitia which compresses the aortic lumen (Fig 1B <jats:xref ref-type="fig" /> ) and a break in the medial wall characterized by bright-blood signal within the AAA (Fig 1C <jats:xref ref-type="fig" /> ). Higher incidence of AAA formation in the vehicle vs. doxycycline group was detected along with a significantly larger (P&lt;.01) AAA area. For mice given USPIO, MRI revealed signal loss in the periphery and shoulder region of the AAA which corresponded to macrophage rich regions as determined by IHC. </jats:p> <jats:p> <jats:bold>Conclusion</jats:bold> These results demonstrate MRI's potential for non-invasively and temporally assessing AAA development and pharmacological intervention in this pre-clinical cardiovascular disease model. </jats:p> <jats:p> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="anchor" xlink:href="zhc141070019837g.jpeg" /> </jats:p>
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits... more Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mech-anism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxi-dation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitor-ing pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake ("64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohy-drate versus fat oxid...
is published by the American Heart Association, 7272Arteriosclerosis, Thrombosis, and Vascular Bi... more is published by the American Heart Association, 7272Arteriosclerosis, Thrombosis, and Vascular Biology
Cui, Douglas T. Thudium, Rogely Boyce, Cynthia L. Burns-Kurtis, Rosanna C. Mirabile, Tian-li Yue,... more Cui, Douglas T. Thudium, Rogely Boyce, Cynthia L. Burns-Kurtis, Rosanna C. Mirabile, Tian-li Yue, Weike Bao, Beat M. Jucker, Juan-li Gu, Anne M. Romanic, Peter J. Brown, Jianqi Ischemia/Reperfusion Injury Protects the Heart From α Activated Receptor− Activation of Peroxisome Proliferator Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2003 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation doi: 10.1161/01.CIR.0000093187.42015.6C 2003;108:2393-2399; originally published online October 13, 2003; Circulation. http://circ.ahajournals.org/content/108/19/2393 World Wide Web at: The online version of this article, along with updated information and services, is located on the
Circulation: Journal of the American Heart Association, 2003
Background—Peroxisome proliferator–activated receptor-&agr; (PPAR-&agr;) is expressed in the hear... more Background—Peroxisome proliferator–activated receptor-&agr; (PPAR-&agr;) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-&agr; in acute ischemia/reperfusion myocardial injury remains unclear. Methods and Results—The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-&agr; agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg · kg−1 · d−1 reduced infarct size by 28% and 35%, respectively (P <0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-&agr;–null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-&agr; and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels...
Circulation, Oct 31, 2006
-/mice (Fig 2) while treatment with SB239063 decreased normalized signal loss in the apoE -/mouse... more -/mice (Fig 2) while treatment with SB239063 decreased normalized signal loss in the apoE -/mouse arch. However, while the Ang II group had significantly higher absolute iron content (↑103%, P<0.001) in the arch compared with the saline group, the Ang II+SB-239063 group did not (↑6%, NS). There was a significant positive correlation between the absolute iron content of the aortic arch and the normalized in vivo MRI signal intensity loss present in the aortic arch (r=0.79, P<0.001). Immunohistochemical localization of iron (Perl’s) and macrophages (Cat-S) within the atherosclerotic lesion can be seen in Fig. 3. Perl’s staining demonstrated that iron accumulation is mainly associated with the macrophages. Conclusion The present study demonstrates that non-invasive assessment of USPIO uptake, as a marker for inflammation in mouse atherosclerotic plaque, is feasible and that p38 MAPK inhibition attenuates the pro-inflammatory uptake of USPIO in the aorta of Ang II infused apoE -/mice. Fig 1 Fig 2 Fig 3
PLOS ONE, 2015
Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits... more Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13 C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O 2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake ("64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation ("14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP ("106%, p<0.05) and lactate ("121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization ("14%, p<0.05) and decreased fatty acid oxidation (#15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.
Journal of Lipid Research, 2005
Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body ... more Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7 ␣-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies. These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.-Groot, P.
Cardiovascular Diabetology, 2013
Background: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting o... more Background: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. Methods: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 μg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C min). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. Results: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. Conclusions: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.
Circulation-cardiovascular Imaging, 2008
Background-Hyperlipidimic mice administered angiotensin II have been used for the study of abdomi... more Background-Hyperlipidimic mice administered angiotensin II have been used for the study of abdominal aortic aneurysms (AAAs). The purpose of this study was to examine the use of MRI for studying AAA development and for examining the effects of pharmacological intervention on AAA development in the apolipoprotein E-deficient mouse. Methods and Results-Suprarenal aortic aneurysms were generated in apolipoprotein E-deficient mice administered angiotensin II (1000 ng/kg per min) for up to 28 days. In vivo MRI was performed serially (once weekly) to assess AAA development and rupture. Comparison of AAA size as measured by in vivo and ex vivo MRI resulted in excellent agreement (rϭ0.96, PϽ0.0001). In addition, MRI correlated with histology-derived AAA area assessment (in vivo versus histology: rϭ0.84, PϽ0.0001; ex vivo versus histology: rϭ0.89, PϽ0.0001). In a separate study, angiotensin II-administered apolipoprotein E-deficient mice were treated with doxycycline (broad-based matrix metalloproteinase inhibitor; 30 mg/kg per day for 28 days). MRI was able to noninvasively assess a reduced rate of AAA development (46% versus 71%, PϽ0.05), a decreased AAA area (2.56 versus 4.02 mm 2 , PϽ0.01), and decreased incidence of rupture (43% versus 100%) in treated versus control animals. Inhibition of aorta matrix metalloproteinase 2/9 activity was observed in the treated animals. Conclusions-These results demonstrate the use of MRI to noninvasively and temporally assess AAA development on pharmacological intervention in this preclinical cardiovascular disease model. (Circ Cardiovasc Imaging. 2008; 1:220-226.)
Objective-Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noni... more Objective-Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation. The purpose of this study was to noninvasively evaluate USPIO uptake in aorta of apoE Ϫ/Ϫ mice and to determine the effects of Angiotensin II (Ang II) infusion and chronic antiinflammatory treatment with a p38 MAPK inhibitor on this uptake. Methods and Results-ApoE Ϫ/Ϫ mice were administered saline or Ang II (1.44 mg/kg/d) for 21 days. In vivo MRI assessment of USPIO uptake in the aortic arch was observed in all animals. However, although the Ang II group had significantly higher absolute iron content (1103%, PϽ0.001) in the aortic arch compared with the saline group, the p38 MAPK inhibitor (SB-239063, 150 mg/kg/d) treatment group did not (16%, NS). The in vivo MRI signal intensity was significantly correlated to the absolute iron content in the aortic arch. Histological evaluation of the aortic root lesion area showed colocalization of USPIO with macrophages and a reduction in USPIO but not macrophage content with SB-239063 treatment. Conclusion-The present study demonstrates that noninvasive assessment of USPIO uptake, as a marker for inflammation in murine atherosclerotic plaque, is feasible and that p38 MAPK inhibition attenuates the uptake of USPIO in aorta of Ang II-infused apoE Ϫ/Ϫ mice. (Arterioscler Thromb Vasc Biol 2008;28:000-000.)
Arteriosclerosis Thrombosis and Vascular Biology, 2010
Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine recept... more Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model. Apolipoprotein E(-/-) mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.
PLOS One, 2011
Background: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been... more Background: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency.
Journal of Lipid Research, 2006
The liver X receptors (LXRs) a and b are responsible for the transcriptional regulation of a numb... more The liver X receptors (LXRs) a and b are responsible for the transcriptional regulation of a number of genes involved in cholesterol efflux from cells and therefore may be molecular targets for the treatment of cardiovascular disease. However, the effects of LXR ligands on cholesterol turnover in cells has not been examined comprehensively. In this study, cellular cholesterol handling (e.g., synthesis, catabolism, influx, and efflux) was examined using a stable isotope labeling study and a two-compartment modeling scheme. In HepG2 cells, the incorporation of 13 C into cholesterol from [1-13 C]acetate was analyzed by mass isotopomer distribution analysis in conjunction with nonsteady state, multicompartment kinetic analysis to calculate the cholesterol fluxes. Incubation with synthetic, nonsteroidal LXR agonists (GW3965, T0901317, and SB742881) increased cholesterol synthesis (z10-fold), decreased cellular cholesterol influx (71-82%), and increased cellular cholesterol efflux (1.7-to 1.9-fold) by 96 h. As a consequence of these altered cholesterol fluxes, cellular cholesterol decreased (36-39%) by 96 h. The increased cellular cholesterol turnover was associated with increased expression of the LXR-activated genes ABCA1, ABCG1, FAS, and sterol-regulatory element binding protein 1c.
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Papers by karpagam aravindhan