| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
/
agonists on HDL-cholesterol in vervet monkeys
* Department of Pathology/Comparative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157
Tularik, Inc., South San Francisco, CA 94080
Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M500002-JLR200
2 Present address of M. Schwarz: F. Hoffmann-La Roche Pharmaceuticals Division, Department of Vascular and Metabolic Diseases, 4070 Basel, Switzerland. 
3 Present address of A. Chai: University of Michigan, School of Pharmacy, 1200 West Stadium Boulevard, #6, Ann Arbor, MI 48103.
1 To whom correspondence should be addressed. e-mail: jmwallac{at}wfubmc.edu
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and PPAR
agonists to increase HDL-cholesterol (HDL-C) in the St. Kitts vervet, a nonhuman primate model of atherosclerosis. Four groups (n = 6) were studied and each group was assigned one of the following "treatments": a) vehicle only (vehicle); b) the PPAR selective agonist GW501516 (GW); c) the PPAR/ agonist T913659 (T659); and d) the PPAR agonist TriCor® (fenofibrate). No statistically significant changes were seen in body weight, total plasma cholesterol, plasma triglycerides, VLDL-C, LDL-C, or apolipoprotein B (apoB) concentrations. Each of the PPAR and PPAR agonists investigated in this study increased plasma HDL-C, apoA-I, and apoA-II concentrations and increased HDL particle size in St. Kitts vervets. The maximum percentage increase in HDL-C from baseline for each group was as follows: vehicle, 5%; GW, 43%; T659, 43%; and fenofibrate, 20%. Treatment with GW and T659 resulted in an increase in medium-sized HDL particles, whereas fenofibrate showed increases in large HDL particles.
These data provide additional evidence that PPAR and PPAR agonists (both mixed and selective) have beneficial effects on HDL-C in these experimental primates.
Supplementary key words animal model • apolipoprotein A-I • apolipoprotein A-II • atherosclerosis • high density lipoprotein particle size • lipoprotein metabolism • nonhuman primate
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, PPAR, and PPAR
, have been identified. All have tissue-specific expression patterns and form heterodimers with the retinoid X receptor to exert their effects on gene transcription (1). A number of excellent reviews describing the emerging roles of PPARs in a variety of biological processes have been published recently (1–6). Among the functions most clearly defined is the role of PPARs as dietary lipid sensors involved in fatty acid and carbohydrate metabolism.
For many years, PPAR and PPAR agonists have been used for the treatment of dyslipidemia and type 2 diabetes, respectively. Fibrates (e.g., fenofibrate, gemfibrozil) have been shown to decrease plasma triglycerides (TGs) and increase high density lipoprotein-cholesterol (HDL-C) through the activation of PPAR, which is primarily expressed in liver, kidney, skeletal muscle, and heart. Glitazone drugs (e.g., rosiglitazone, pioglitazone) exert their antidiabetic effects through the activation of PPAR, which is found predominantly in adipocytes and macrophages (1–3). Less is known about the function of PPAR, which has broad tissue distribution, although emerging data also support a role in lipid homeostasis (7, 8) and fatty acid oxidation (3). Recently, the selective PPAR agonist GW501516 (GW) was shown to decrease plasma TG levels and increase HDL-C concentrations in a nonhuman primate model of obesity and type II diabetes (7).
Currently, there are very few therapeutic drugs available to increase HDL-C concentrations in patients with levels considered to put them at risk for atherosclerotic heart disease (<40 mg/dl for men, <50 mg/dl for women) (9). Of the treatments available, PPAR agonists are among the most promising drug candidates to target this treatment gap (10). Indeed, the observation that PPAR and PPAR agonists increase HDL-C in humans and/or animal models has enhanced interest in these two receptors as candidate targets for pharmacological intervention aimed at the treatment of dyslipidemias. The objective of this study was to characterize and compare a novel PPAR/ agonist with two known PPAR agonists, GW and Tricor®, with respect to HDL-C increasing efficacy in vervet monkeys, a nonhuman primate model of atherosclerosis (11–13).
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
55 months, during which time plasma lipid parameters and body weights were regularly monitored. Twelve animals from each dietary group were used in this study. Animals were housed in individual cages throughout the period of study in a facility accredited fully by the Association for the Assessment and Accreditation of Laboratory Animal Care, International. Procedures were conducted in accordance with the Federation of American Societies for Experimental Biology's Principles for the Use of Animals in Research and Education, and were approved by the Wake Forest University Institutional Animal Care and Use Committee.
Twenty-four monkeys were assigned to four equivalent treatment groups (n = 6) using pretreatment body weight, total plasma cholesterol, HDL-C, and dietary group as randomization variables. Three animals fed either type of dietary fat were included in each treatment group. Each group was then assigned one of the following four "treatments": a) vehicle only (vehicle); b) the PPAR selective agonist GW (GW) (7); c) the PPAR/ agonist T913659 (T659); and d) the PPAR agonist TriCor® (fenofibrate; Abbott Laboratories, Abbott Park, IL).
Oral administration of compounds was done by creating a suspension of each drug in vehicle, an aqueous mixture of NesquikTM strawberry powder (Nestlé USA, Inc., Glendale, CA) and Carnation® nonfat dry milk (Nestlé USA). Briefly, each compound was weighed and ground with the nonfat dry milk and then mixed with NesquikTM (91 g/l water) on a stir plate for at least 30 min. Doses were divided into aliquots with volumes (20 ml) proportional to body weight and served immediately, just before the afternoon meal. All animals drank their doses without hesitation.
Food (70 kcal/kg/day) was weighed into morning and afternoon meals and consumption was monitored daily, with notations being made if an animal occasionally had food left over from a previous meal.
The experiment was a 19 week dose-escalating study that consisted of 1 week of baseline, 12 weeks of treatment, and 6 weeks of "washout." During baseline, monkeys in all four groups were administered vehicle once daily for 7 days per week. Test compounds other than fenofibrate were then administered in vehicle at a dose of 0.1 mg/kg once daily for 3 weeks, 1.0 mg/kg once daily for 3 weeks, and 3.0 mg/kg once daily for 6 weeks. The fenofibrate group was administered 10 mg/kg once daily for the first 3 weeks of treatment and then increased to 30 mg/kg once daily for the remaining 9 weeks of treatment. At the completion of treatment, monkeys in all groups were administered vehicle once daily and monitored for an additional 6 weeks.
Animals were sedated with ketamine HCl (10 mg/kg) for body weight measurements and blood collection at weeks 1, 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, and 19 of the study. Specifically, total plasma cholesterol, HDL-C, TG, and plasma exposure levels of each compound were measured at baseline, at least twice at each dose during the dose period (four times at the highest dose), and three times during the washout period. Cholesterol distribution among lipoprotein classes using gel filtration and ELISAs for apolipoprotein A-I (apoA-I), apoA-II, and apoB was measured at baseline and at least once at the end of each dose period. A final evaluation of lipoprotein cholesterol distribution was done at week 16, after 3 weeks of washout. To monitor the health of the animals, liver enzymes (serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, and -glutamyltranspeptidase) and a complete blood count with differential were done at baseline, at least once at the end of each dose period (twice during the highest dose), and twice during the washout period (liver enzymes only).
Reagents
All test material was obtained from Tularik, Inc. (South San Francisco, CA). GW and fenofibrate are well-characterized PPAR and PPAR agonists, respectively. T659 (Fig. 1)
emerged as a high-affinity PPAR/ agonist from a medicinal chemistry optimization effort. Radioligand binding and cellular assays using CV-1 cells were performed as described (14). For the cellular assays, Effectene (Qiagen, Inc., Valencia, CA) was used as the transfection agent, and test compounds were added for 20 h before measuring luciferase activity.
|
5 h before daily compound administration. Blood was collected into sterile evacuated tubes containing 0.1% EDTA and 0.1% NaN3 and placed immediately on ice. Plasma concentrations of test compounds were determined by HPLC-MS in the Department of Drug Metabolism and Pharmacokinetics at Tularik, Inc. Lipid, lipoprotein, and apolipoprotein analyses were conducted using methods described previously (11, 15). Briefly, plasma was separated by centrifugation at 2,000 g for 30 min at 4°C. Protease inhibitor cocktail (Sigma PZ714; Sigma-Aldrich, Inc., St. Louis, MO) was added to the isolated plasma, and total cholesterol and TGs were determined using enzymatic measurements (16, 17). Plasma lipoprotein cholesterol distributions were determined by gel filtration chromatography of whole plasma on a Superose 6 fast-protein liquid chromatography column (30 x 1 cm; Pharmacia Corp., Peapack, NJ) with on-line cholesterol determination using a modification of the method of Kieft, Bocan, and Kraus (18). Apolipoprotein concentrations were measured using a noncompetitive sandwich ELISA with monospecific goat anti-monkey antibodies to apoA-I, apoA-II, and apoB (15).
HDL particle size determinations
To determine HDL particle size, apoA-I distribution in whole plasma was estimated using nondenaturing gradient gel electrophoresis, Western blotting, and scanning with a ChemiImagerTM 5500 (Alpha Innotech Corp., San Leandro, CA). Briefly, the material from the polyacrylamide gel was blotted onto nitrocellulose and subsequently probed with goat antiserum raised against monkey apoA-I. Horseradish peroxidase-conjugated anti-goat IgG 31402 (Pierce, Rockford, IL) was used as the secondary antibody. Peroxidase signal was detected using SuperSignal® West Pico Chemiluminescent Substrate (Pierce, Rockford, IL) and captured on X-Omat film (Eastman Kodak, New Haven, CT). Images were scanned and quantified using the ChemiImager ID-Multilane densitometry analysis tool. Each lane was divided into areas representing small (two apoA-I), medium (three apoA-I), and large (four apoA-I) HDL particles using break points that corresponded to Stokes radius cutoffs of <4.2, 4.2–5.8, and >5.8 nm, respectively (19). Band intensity for each area was quantified and reported as a percentage of total apoA-I signal.
Statistical analyses
Data were tested for normality using the Kolmogorov-Smirnov test for normality and an equality of variances F-test. Health parameters were evaluated using repeated-measures ANOVA. Lipid and lipoprotein parameters were evaluated similarly and, when significant differences were found, subjected to subsequent analyses using paired t-tests to compare baseline values with values collected after 6 weeks of treatment at the highest dose administered (for fenofibrate, after 9 weeks at the highest dose).
To identify differences in HDL particle size distribution, the percentages were estimated for apoA-I in small, medium, and large HDLs after gel electrophoresis and Western blotting of whole plasma. The apoA-I concentrations in small, medium, and large particles were then calculated from whole plasma apoA-I concentration, and differences were evaluated for statistical significance using repeated-measures ANOVA.
The levels of statistical significance for identified differences were determined according to the formulae provided with the statistical software (Statview, version 5.0.1; SAS Institute, Inc., Cary, NC). Differences were considered significant at P 
0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, PPAR, and PPAR with inhibition constants of 3, 90, and 420 nM, respectively. The subtype specificity of T659 was confirmed in cell-based transactivation assays, in which it activated PPAR, PPAR, and PPAR with EC50 values of 9, 510, and 1,300 nM, respectively. Thus, T659 is a very potent PPAR agonist that also activates PPAR and, to a lesser extent, PPAR.
|
, liver X receptor ß, farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and estrogen receptor (data not shown). Additional criteria for selection of this compound for in vivo evaluation in the vervet nonhuman primate model were metabolic stability, low protein binding, favorable pharmacokinetic properties, lack of toxicity in rats, and HDL-C-increasing efficacy in rodent models of dyslipidemia (data not shown). In mice lacking a functional PPAR gene, 60% of HDL-C-increasing efficacy compared with wild-type controls was maintained, indicating that this effect was mediated in large part through the activation of PPAR (data not shown).
Efficacy in vervets
All drugs were absorbed efficiently throughout the course of the study, with plasma steady-state trough concentrations increasing as a function of compound dose (data not shown). After 10 weeks of dosing, trough plasma levels of T659 were 4-fold higher than levels of GW and 300-fold higher than the EC50 value for the activation of PPAR in the cell-based transactivation assay.
There were no statistically significant effects of treatment on body weight in any of the groups that completed the 19 week study (data not shown). The effects of the PPAR agonists on other health parameters are shown in Table 1. Briefly, animals in the T659 group had significant decreases in all red blood cell parameters, including red blood cell count, hemoglobin concentration, and hematocrit. All red cell values had returned to normal by the end of the 6 week washout. The parameters measured were not such that the type of anemia could be reliably classified. Significant increases were also seen in white blood cell counts of animals in the T659 group, although all values remained within the normal range for adult male vervets (International Species Information System, Apple Valley, MN). Animals in the GW group showed a statistically significant decrease in serum glutamic oxaloacetic transaminase and -glutamyltranspeptidase; no changes in liver enzymes were observed in any of the other groups.
|
|
agonists in this study caused increases in apoA-I concentrations in the medium-sized HDL particles. For the PPAR agonist fenofibrate, the trend for an increase in apoA-I in medium-sized particles was not statistically significant. However, a significant trend for apoA-I to increase in large HDL particles was present. At no time in any of the groups was an increase in the concentration of small HDLs observed.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and PPAR agonists have been used for a number of years to treat metabolic syndrome and type 2 diabetes, respectively. However, these drugs, like statins, are limited in their ability to increase HDL-C (10, 20). Although fibrates are known to cause slight increases in HDL-C concentration, glitazone drugs have little or no effect on HDL-C (10, 20). The emerging role of PPAR in lipid metabolism (7, 21) and the demonstrated ability of PPAR agonists to increase HDL-C in animal models (7, 22) have enhanced interest in this receptor as a target for the therapeutic intervention of dyslipidemias. More potent PPAR agonists and/or agonists with mixed receptor selectivity are thought to have significant potential as novel antiatherosclerotic agents (19, 20).
In this study, selective PPAR and PPAR compounds, and a compound with mixed PPAR/ selectivity, increased plasma HDL-C, apoA-I, and apoA-II concentrations in St. Kitts vervets. The percentage increase in HDL-C from baseline for treatment groups ranged from 20% to 43%, with the greatest increases seen in groups treated with agonists with mixed PPAR/ receptor selectivity. GW and T659 showed similar biochemical and cellular potency for PPAR binding and activation and caused a similar increase of HDL-C in vervet monkeys, but the plasma trough concentration of T659 was on average 4-fold higher than that of GW at each time point measured. The lack of an effect on fasting insulin and glucose levels (data not shown) suggests that the in vitro potency of T659 for PPAR activation did not translate into a metabolic effect in this model.
These findings confirm and expand previous reports of increased plasma HDL-C in obese prediabetic primates treated with the PPAR agonist fenofibrate (23) or the same selective PPAR agonist (GW) used in this study (7). Unlike in previous reports, the St. Kitts vervets in this study were fed fat-enriched atherogenic diets and had naturally low plasma TG concentrations that were unaffected by treatment with the selective and mixed PPAR/ agonists evaluated here. This is not unexpected, because the previous studies showing a decrease in TG were done in a rhesus monkey model of obesity and type 2 diabetes in which the diet was a low-fat chow. Affected rhesus monkeys are atypical in that they have aged to the point that they become hyperinsulinemic and hypertriglyceridemic, even in a prediabetic state (23). In contrast, most monkeys fed fat-enriched diets have very low plasma TG concentrations, presumably as a result of the induction of lipoprotein lipase by the dietary fat (24). The tight inverse relationship observed between plasma concentrations of HDL-C and TG makes the HDL-C increases in this study even more striking, because they occurred in the face of normal plasma TG concentrations that were unaffected by treatment.
The measures of HDL particle size found in vehicle and treated vervets suggest that PPAR agonists, both and , favor the production of larger HDL particles in primates. Previous experiments in our laboratory have shown that small, medium, and large HDL particles typically contain two, three, and four apoA-I molecules per particle, respectively, and there is a unidirectional maturation in the plasma from small to medium and small to large HDL particles (19). The larger HDL particles are cleared from plasma preferentially by the liver (25). The shift toward increased amounts of medium and large particles as seen in animals treated with GW, T659, and fenofibrate suggests that PPAR/ agonists may be involved in the process by which HDL particles acquire cholesterol, apoA-I, and apoA-II and are matured in plasma. In humans, small HDL particles are associated with coronary artery disease progression and larger HDL particles are thought to be protective (26).
The mechanism for the observed increases in plasma HDL-C concentration and larger apoA-I HDL particles seen here in nonhuman primates treated with PPAR/ agonists has yet to be determined, but presumably it involves an enhanced capacity for reverse cholesterol transport by HDL in treated animals. In the presence of PPAR and PPAR agonists, the ability of apoA-I to be assembled into larger HDLs for cholesterol transport may be promoted, presumably indicating that the availability of apoA-I for HDL particle assembly is higher (27). PPAR agonist effects on the transcription of key proteins involved in reverse cholesterol transport are of interest given the relative paucity of pharmacological agents known to promote HDL-C concentrations. PPAR has been shown previously to mediate fibrate action on HDL-C levels via transcriptional induction of the synthesis of the major apolipoproteins of HDL as well as LPL (28, 29). Fibrates have been reported to upregulate ABCA1 (30) and scavenger receptor class B type I (SR-BI) (31) expression in human monocytes and macrophages and to decrease hepatic apoC-III transcription (2). More recently, fibrate treatment was found to suppress hepatic SR-BI protein expression in mice without changing SR-BI mRNA levels (32). The reduced SR-BI protein expression in fibrate-treated mice correlated with enlarged HDL particle size. When hepatic SR-BI levels were normalized by recombinant adenoviral gene transfer, the fibrate-induced HDL enlargement was abolished, suggesting a role of SR-BI in the formation of large HDL particles (32).
Less is known about the potential role of PPAR in reverse cholesterol transport, because there are fewer receptor-specific agonists available for study. In vitro cholesterol-loading studies have generated conflicting results. In one study, the PPAR agonist GW was found to promote cholesterol efflux in multiple tissues by increasing expression of the reverse cholesterol transporter ABCA1 (7). In another study involving a different selective PPAR agonist, total macrophage lipid accumulation was increased, despite an increase in ABCA1 expression, apparently as a result of a relative upregulation of class A and B scavenger receptors and adipophilin and repression of other key genes involved in lipid efflux (21). The extent to which the different agonists used may explain the observed differences cannot be determined. More recently, comparison of PPAR–/– and wild-type bone marrow revealed no differences in cellular cholesterol balance, leading the authors to conclude that PPAR does not appreciably modulate either cholesterol uptake or efflux (33). Studies in genetically obese mice (Leprdb/db) and transgenic mice with selective expression of an active form of PPAR in adipose tissue reveal interesting parallels between PPAR and PPAR, and coupled with in vitro data, they suggest that PPAR may also be an important promoter of fatty acid oxidation and energy uncoupling (34). The key enzyme involved in the hydrolysis of TG, LPL, has been implicated in the generation of endogenous PPAR and PPAR ligands (29) and is known to correlate positively with HDL-C levels (35). Whether PPAR- and PPAR-mediated lipolysis drives reverse cholesterol transport by increasing the availability of HDL-associated apoA and apoC in plasma is unknown.
Clearly, additional studies are needed to determine the complex mechanism by which PPAR and PPAR agonists influence lipid metabolism in a manner that results in beneficial effects on HDL-C concentration and particle size. A caveat that must be considered, however, is that many of the published studies have been done in mice, and for unknown reasons the responsiveness of rodent models to PPAR agonists is not typical of that in primates. One explanation may be found in the observation that PPARs induce human apoA-I gene expression in vivo via a positive PPAR response element (PPRE) located in the apoA-I promoter A site (36). A three nucleotide difference renders the positive PPRE nonfunctional in rodents. The beneficial effect of PPARs observed in apoE-deficient mice overexpressing human apoA-I (37), but not in other mouse models (37, 38), lends support to the premise that a difference in rodent apoA-I PPRE is responsible for the observed variability in rodent responsiveness to PPAR agonists. Using sequence alignment software, we have determined that the PPRE sequence in African green (vervet) and cynomolgus monkey apoA-I is identical to that of human apoA-I. Therefore, it is reasonable to assume that individual PPARs (, , and ) activate vervet monkey apoA-I in a manner analogous to that of human apoA-I. Whether this mechanism is responsible for the improved HDL profiles seen in vervets in this study is unknown. However, the similarity between human, cynomolgus, and vervet apoA-I PPRE suggests that primates are good models for future investigations of the effects of PPARs on human HDL metabolism and atherosclerosis.
In summary, each of the PPAR and PPAR agonists investigated in this study appeared to increase plasma HDL-C, apoA-I, and apoA-II concentrations and increase HDL particle size in St. Kitts vervets. Whether these changes were the result of increased production or decreased clearance of HDL-C is only a matter of speculation at this time and will require further work. However, these data provide additional evidence that PPAR and PPAR agonists (both mixed and selective) have beneficial effects on HDL-C in primates. With respect to increasing HDL-C, GW and fenofibrate were as efficacious in the vervet monkey as reported for obese rhesus monkeys (7, 23). Thus, the vervet can be considered a valid primate model in which to conduct future investigations of the therapeutic potential of PPAR and PPAR agonists for the treatment of dyslipidemias and the mechanism(s) behind the observed effects on plasma HDL-C concentrations.
|
ACKNOWLEDGMENTS |
|---|
Manuscript received January 3, 2005 and in revised form February 8, 2005.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and cancers. Clin. Cancer Res. 9: 1–9. agonists on central nervous system inflammation. J. Neurosci. Res. 71: 315–325.[CrossRef][Medline]
alters lipid metabolism in db/db mice. FEBS Lett. 473: 333–336.[CrossRef][Medline]
and PPAR- activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med. 7: 53–58.[CrossRef][Medline]
. Science. 302: 453–457. activates fat metabolism to prevent obesity. Cell. 113: 159–170.[CrossRef][Medline]
and Rev-erb mediate the species-specific regulation of apolipoprotein A-I expression by fibrates. J. Biol. Chem. 273: 25713–25720.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  B. G. Shearer, D. J. Steger, J. M. Way, T. B. Stanley, D. C. Lobe, D. A. Grillot, M. A. Iannone, M. A. Lazar, T. M. Willson, and A. N. Billin Identification and Characterization of a Selective Peroxisome Proliferator-Activated Receptor {beta}/{delta} (NR1C2) Antagonist Mol. Endocrinol., February 1, 2008; 22(2): 523 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Hollingshead, R. L. Killins, M. G. Borland, E. E. Girroir, A. N. Billin, T. M. Willson, A. K. Sharma, S. Amin, F. J. Gonzalez, and J. M. Peters Peroxisome proliferator-activated receptor- /{delta} (PPAR /{delta}) ligands do not potentiate growth of human cancer cell lines Carcinogenesis, December 1, 2007; 28(12): 2641 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Hautala, A. S. Leon, J. S. Skinner, D. C. Rao, C. Bouchard, and T. Rankinen Peroxisome proliferator-activated receptor-{delta} polymorphisms are associated with physical performance and plasma lipids: the HERITAGE Family Study Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2498 - H2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Sprecher, C. Massien, G. Pearce, A. N. Billin, I. Perlstein, T. M. Willson, D. G. Hassall, N. Ancellin, S. D. Patterson, D. C. Lobe, et al. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor {delta} Agonist Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 359 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Gilde, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A24 - A32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Lee and J. Plutzky Liver X Receptor Activation and High-Density Lipoprotein Biology: A Reversal of Fortune? Circulation, January 3, 2006; 113(1): 5 - 8. [Full Text] [PDF]
|
|
|
|
|
|
F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
