| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Metabolic and Cardiovascular Drug Discovery (G.J.G., D.M.E., P.G.S., B.C.B.), Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534; and Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology (N.-H.N., T.S.S.) and the Metabolic Research Unit (J.D.B.), University of California, San Francisco, San Francisco, California 94143
Address all correspondence and requests for reprints to: Gary J. Grover, Ph.D., Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534. E-mail: groverg{at}bms.com.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4%) reduction in body weight in these animals. Therefore, selective TRß activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a). |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, TRß) have been identified and are the products of distinct genes (4, 5). The TR1 and TRß1 isoforms are ubiquitously expressed, although TR1 predominates in heart (70% of TRs), whereas TRß1 predominates in the liver (80% of TRs) (6).
Studies in patients with the syndrome of resistance to thyroid hormone who have mutations in TRß, suggest that TR regulates heart rate (1). This notion is supported by studies using TR1-/- mice, suggesting that the effects of TR agonists on heart rate are mediated by TR1 activation, whereas cholesterol-lowering is mediated primarily by TRß1 activation (5, 7). Interestingly, these investigators also showed that body temperature is modulated by TR.
The TRß selective agonist GC-1 (10-fold higher binding affinity for TRß1 vs. TR1) reduces cholesterol in rodents with a more than 20-fold selectivity compared with tachycardia (8). Whereas GC-1 is 10-fold more TRß selective, it enters cardiac tissue 30-fold less efficiently than T3, suggesting that selective tissue uptake may also explain its selective cholesterol-lowering action. Nevertheless, it is likely that each TR isoform mediates distinct functions, and that the selective cholesterol lowering action of GC-1 is at least in part a result of TRß activation (8). No studies on the effects of GC-1 on metabolic rate have been performed so information on the potential antiobesity effects of this and related agents are currently unclear. The potential for an agent with combined lipid-lowering and antiobesity activity is great because a large fraction of obese individuals may also present with undesired lipid inventories.
Little is known about the role of TRß in mediating the increased metabolic rate seen with thyroid hormone treatment. Work from several laboratories showed variable results for a potential role for TRß in control of metabolic rate (9, 10). Studies from our laboratories showed a 10-fold selectivity for therapeutic (5–10%) increases in metabolic rate in TR1-/- mice (10). In addition, the TRß selective agonist KB-141 (10-fold selective for binding TRß vs. TR) (10) displayed a similar profile in cholesterol-fed rats. This suggests the possibility that TRß activation plays a role in increasing metabolic rate and that selective TRß activation may have therapeutic advantages compared with nonselective TR agonists. It is possible that the combination of the TRß selectivity of GC-1 with its selectivity for noncardiac tissue uptake could make it especially advantageous because KB-141 does not show selective tissue uptake (10).
The goal of this study was to determine the relationship between metabolic rate, heart rate, and cholesterol lowering in cholesterol-fed rats and cynomolgus monkeys after GC-1 and T3 treatment, and to determine whether GC-1 will have an improved therapeutic window compared with T3 for regulating these parameters. Cynomolgus monkeys were used because of their potential for showing weight reduction (they are in a stable growth phase) as well as having a lipid metabolic profile more consistent with that of man. The results from this study show that in rats, GC-1 increases metabolic rate with a shallow dose-response curve compared with T3 and is approximately 10-fold more selective than T3 for therapeutic increases in metabolic rate without tachycardia. In addition to retention of cholesterol-lowering activity in rats and primates, GC-1 reduced levels of lipoprotein (a) [Lp(a)] and body weight in primates, which further underscores the potential therapeutic utility of such selective thyromimetics.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Cholesterol-fed rats
Male Sprague Dawley rats (Harlan, Indianapolis, IN) were fed a diet containing 1.5% cholesterol and 0.5% cholic acid (Harlan Teklad Rodent Chow, Harlan Teklad, Madison, WI) for 2 wk, after which they were treated once daily with one of several doses of GC-1 or T3 (Sigma Chemicals, St. Louis, MO) or vehicle (10% m-pyrol, 5% ethanol, 5% cremaphor, 80% water, n = 5–6 /group) by oral gavage for 7 d (this vehicle was used for all studies) as described previously (8). T3 was given over a dose range of 1.54–154 nmol/kg·d and GC-1 was given over a range of 46.2–27700 nmol/kg·d. Higher doses of GC-1 were used because it has a 10-fold lower ED50 for activation of TRß compared with T3 (8). The doses of T3 were chosen starting with 1 µg/kg·d (1.54 nmol/kg·d), and the doses were transposed to molar doses so that appropriate comparisons with GC-1 could be made.
After 7 d of drug treatment, oxygen consumption (MVO2) was then measured in conscious rats using Oxymax chambers (Columbus Instruments, Columbus, OH) as previously described (11, 12). Briefly, the animals were kept in the chambers for 6 h where they were allowed to rest. The studies were performed at approximately the same time each day (morning, 5 h after last dosing) and the rats were always inactive under these conditions. After completion of MVO2 measurements, the animals were anesthetized with ip sodium pentobarbital (30 mg/kg), and heart rates were measured using lead II ECG (Gould Instruments, Valley View, OH). Blood was collected from the inferior vena cava and analyzed for plasma cholesterol, TSH: thyroid stimulating hormone, and blood chemistries (liver enzymes, electrolytes, blood urea nitrogen:BUN, creatine kinase, creatinine, etc.) as described previously (8, 10). Briefly, the blood samples were centrifuged at 2000 rpm for 20 min and the plasma was tested for cholesterol using a Cobas Mira S analyzer (Roche, Indianapolis, IN) and TSH using an RIA kit designed for rat (Amersham Pharmacia Biotech, Arlington Heights, IL) as described previously (8). As stated earlier, GC-1 is a thyromimetic with approximately 10-fold selectivity for TRß (structure shown in Fig. 1
) (13).
|
Studies in cynomolgus monkeys
Female cynomolgus monkeys (3–5 kg) were dosed with vehicle (n = 10 per group), GC-1 at 154 or 924 nmol/kg·d, (n = 5 per group) or T3 (46.2 nmol/kg·d, n = 5 per group) by oral gavage once daily for 7 d. The animals were weighed daily and were gavaged under modest restraint. After the seventh daily dose, 5 h were allowed to transpire and the animals were then prepared for final studies. The animals were lightly anesthetized with ketamine (3–5 mg), and blood pressure and heart rate were determined using a pressure cuff at the base of the tail. Blood samples were then taken at this time for analysis of cholesterol using the Cobas analyzer and blood chemistries, including blood urea nitrogen (BUN), liver transaminases [alanine aminotransferase (ALT), aspartate aminotransferase (AST)]. Lp(a) was measured using a reagent kit from Kamiya Biomedical Co. (Seattle, WA) as described previously (10). The reagents were as follows: reagent 1 = buffer Tris(hydroxymethyl)aminomethane; reagent 2 = antihuman Lp(a) goat antiserum. The assay is performed on a Roche Hitachi Modular Chemistry Analyzer. When a serum sample was mixed with antihuman Lp(a) antiserum, agglutination was caused by the antigen-antibody reaction. The turbidity was measured at 340 nm and 700 nm and is proportional to the Lp(a) in the sample.
Cholesterol in primates primarily exists in the form of low density lipoprotein (LDL) and therefore, no cholesterol feeding was necessary, unlike rats, which ordinarily contain primarily high-density lipoprotein (HDL) cholesterol (14, 15, 16). Thyroid hormones reduce cholesterol levels, in part, by up-regulation of LDL receptors, as well as increasing cholesterol breakdown (1). Previous studies in humans suggested the possibility that thyroid hormones can reduce the risk factor Lp(a) (17), and this was examined in the monkeys for both T3 and GC-1.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Both T3 and GC-1 reduced cholesterol in a dose-dependent manner, with GC-1 being approximately 10-fold less potent, which is consistent with previously reported findings (8). The total cholesterol in cholesterol-fed control rats was 197 ± 26 mg/dl. The maximal degree of cholesterol lowering was similar for both compounds, and this was between an 80–90% reduction compared with the control animals. Triglyceride levels were not reduced (data not shown). The potency for cholesterol-lowering for T3 and GC-1 is shown in Table 1. The ED50 (dose in nmol/kg·d causing 50% reduction in cholesterol) was 20.6 nmol/kg·d for T3 and 190 nmol/kg·d for GC-1. ED50 was selected as an index of potency for cholesterol lowering as this is approximately within the middle (linear) part of the dose-response curve.
|
|
. The baseline value for heart rate was 388 ± 9 beats per min in control animals. GC-1 caused a significant increase in heart rate only at the highest dose of 10,000 nmol/kg·d. The potency index for inducing tachycardia is expressed as an ED15 (Table 1); a 15% increase in heart rate is considered the highest clinically acceptable level of tachycardia resulting from drug treatment (8). GC-1 was significantly more selective for cholesterol lowering compared with tachycardia as demonstrated by the potency ratios of ED15 heart rate/ED50 for cholesterol lowering (Table 2). Cholesterol was reduced with an 18-fold selectivity (when normalized for T3) compared with tachycardia and this is consistent with TRß selectivity for GC-1. TSH (ED30 = 9.8 and 190 nmol/kg·d for T3 and GC-1, respectively; Table 1) was reduced in parallel with cholesterol, which is consistent with TRß control for these parameters, and this is shown by similar potency ratios (Table 2 and Fig. 3).
|
|
). MVO2 in control rats was 1110 ± 28 ml O2/kg·h. MVO2 and heart rate were increased in a parallel manner by T3. GC-1 increased MVO2 in a dose-dependent manner (Fig. 2), although with reduced potency and slope (P < 0.05) compared with T3. Interestingly, there is a 10-fold window of doses (between 100 and 1000 nmol/kg·d) for GC-1 in which modest (5–10%) increases in metabolic rate are observed. A similar window is not seen in the dose-response curve for T3 because of its steep slope.
The relationship between heart rate and MVO2 is shown by the potency ratios for these parameters (Table 2). The potency ratios for heart rate vs. metabolic rate showed no selectivity for T3, whereas GC-1 was approximately 10-fold more selective for modest (and probably therapeutically relevant) increases in MVO2 vs. tachycardia. These data show that GC-1, but not T3, can increase MVO2 within the theoretical therapeutic dose range without producing the undesired side effect of tachycardia.
GC-1 reduced TSH within the therapeutic dose range and therefore we measured serum and tissue T4 and T3 levels. Because RIAs could not be used due to cross-reactivity between GC-1 and the antithyroid hormone antibodies, the less-sensitive LC/MS assay was used. Control animals and 462 nmol/kg·d GC-1-treated animals were used. The 462 nmol/kg·d dose of GC-1 was chosen as it was within the efficacious dose range for cholesterol-lowering and increased MVO2. Serum T4 was significantly reduced from 16.0 ± 2.0 ng/ml in controls to 10.3 ± 1.2 ng/ml by GC-1. Serum and tissue T3 levels are shown in Table 3. T3 was reduced in serum by GC-1 although this reduction was not statistically significant. Liver, brain, and cardiac levels of T3 were not significantly affected by GC-1. Whereas 7 d treatment with GC-1 reduces serum T4, tissue levels of T3 are maintained, and therefore the animals were most likely not hypothyroid, at least in the tissues sampled. In addition, no evidence of systemic hypothyroidism was observed in the any of the GC-1-treated animals.
|
). The reduction in cholesterol was statistically significant for GC-1 whether the data were pooled or analyzed individually for both doses. The reduction in cholesterol was primarily due to a reduction in LDL cholesterol. Along with cholesterol-lowering, Lp(a) levels were significantly reduced by approximately 50% by both T3 and GC-1. The baseline values for Lp(a) were 35 ± 7, 32 ± 4 and 34 ± 6 mg/dl for vehicle, T3 and GC-1-treated groups, respectively, and are similar to previously reported values for monkeys (10). Blood pressure was not affected by either T3 or GC-1 in this study (mean arterial blood pressure = 71 ± 4, 75 ± 5, and 72 ± 4 mm Hg for vehicle, GC-1 and T3, respectively, at the end of the study).
|
). The percent change in body weight was calculated from the paired pre-drug value for each animal. Mean vehicle (at beginning of study) group body weights were 4.8 ± 0.04 kg and were not different from the pre-drug values for T3 and GC-1 groups. Vehicle group weights were unchanged after 1 wk (4.8 ± 0.04 kg). The 1-wk treatment with GC-1 and T3 caused weight loss on the order of 3–4%, which is significantly different from pre-drug values (P < 0.05). This observed change in body weight is similar to that seen previously for T3 treatment (10). The animals were fed ad libitum, and no changes in food intake were observed. In addition, normal blood chemistries, including electrolytes, liver enzymes, BUN, creatine kinase, creatinine, lactate dehydrogenase, etc. were observed, suggesting that the animals were otherwise healthy and that the weight loss was not due to sickness or wasting. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
One approach for developing selective thyromimetics for treatment of hyperlipidemia and obesity is to develop TRß-selective agonists (13). Recent data suggest differential function for TR and TRß that may depend on isoform tissue localization or on true isoform functional differences (8, 23). Data collected from various TR knockout mice suggest the importance of TRß in mediating the cholesterol-lowering and TSH suppressant effects of T3 (5, 7, 8, 24). Studies using the relatively TRß selective thyromimetic GC-1 suggest selective effects of this agent on cholesterol reduction relative to cardiac acceleration (8). The degree of selectivity for cholesterol reduction vs. tachycardia is consistent with the degree of TRß selectivity (8). From these data, one can conclude that TRß selective thyromimetics such as GC-1 may be useful for lowering cholesterol at doses that are devoid of cardiac toxicity. Data reported in the same paper (8) showed that, in addition to TRß selectivity, GC-1 has a different tissue distribution than T3. GC-1 was not taken up as avidly by the heart as T3, although both compounds were taken up by the liver in an equivalent manner. It is not clear whether this tissue distribution difference could partially explain the pharmacological differences between T3 and GC-1 in terms of cholesterol vs. heart rate effects, although differential tissue uptake has been demonstrated for the first-generation selective thyromimetics such as SKF-94901 (23). A new thyromimetic, KB-141, has a similar TRß selectivity profile to GC-1 while having a similar tissue distribution pattern to that of T3. KB-141 shows an approximately 20-fold selectivity for cholesterol-lowering vs. tachycardia, suggesting that in the absence of differential tissue uptake, TRß selective activation is sufficient for cardiac-sparing, cholesterol-lowering thyromimetic action (10, 25).
Unfortunately, less is known about the relative role of TR isoforms in control of metabolic rate. Studies from Vennstrom’s group (5, 7) suggest that metabolic rate (as measured by body temperature) is controlled primarily by TR, and additional studies have shown mixed results for a role for TRß (9, 10). Studies from our laboratory using the TRß-selective KB-141 and TR1-/- mice suggested that TRß activation does reduce cholesterol and increase MVO2 without tachycardia within the therapeutic metabolic rate range (10, 25). Because GC-1 has a similar TRß selectivity as KB-141 plus a potentially more desirable tissue distribution, the pharmacological profile of this compound was examined. Specifically, we compared the MVO2 changes to changes in cholesterol and heart rate.
Detailed studies were performed in rats first because MVO2 can be readily measured, although rats must be cholesterol fed to increase LDL cholesterol concentrations to observe cholesterol reduction by thyromimetics (23). After cholesterol feeding, LDL cholesterol goes up to 90% of total cholesterol in rats. T3 reduced cholesterol as shown previously (8) and the dose-response curve for this was steep. In addition, T3 caused profound increases in both MVO2 and heart rate. Because the undesired tachycardia paralleled the increase in MVO2, there was no window in which safe, therapeutic MVO2 changes could be seen. This is consistent with the poor history of T3 for treating obesity due to cardiac acceleration as well as peripheral tissue wasting (26, 27, 28).
On the other hand, GC-1 had a 10-fold window for therapeutic MVO2 changes without concomitant tachycardia. This demonstration of a window for modest MVO2 increases without cardiac side-effects with GC-1 suggests it is possible to develop thyromimetics possessing safe and efficacious antiobesity activity. Similar MVO2 increases without tachycardia were seen with KB-141, a thyromimetic that penetrates the heart more efficiently than GC-1 (10). Because the common feature for KB-141 and GC-1 is their TRß selectivity, it seems likely that selective TRß activation is the predominant mechanism for increasing MVO2 without inducing tachycardia for these compounds. TSH was reduced in parallel with cholesterol by both GC-1 and T3, and it should be noted that some TSH suppression was observed within the theoretical therapeutic range for GC-1. It is not presently known whether this would limit the potential utility of this compound because of regional hypothyroidism. We found no evidence for hypothyroidism, although we did not look at all tissues, and further work is required to show this, including more detailed time course studies.
To further characterize GC-1 pharmacologically, we determined its effect on cynomolgus monkeys as their lipid metabolism more closely resembles that of man. In addition, we have found that thyromimetics effectively cause weight loss in this species within a short period of time, and this can be readily compared with cardiac activity (10). In this study, GC-1 reduced cholesterol by approximately 35–40% at both a low and high dose. This cholesterol lowering efficacy is comparable to that seen for 3-hydroxy-3-methylglutaryl (HMG)-Coenzyme A reductase inhibitors such as pravastatin in primates (28). In addition to cholesterol reduction, Lp(a) levels were reduced by approximately 50% with GC-1 treatment. Although similar changes in lipid profiles were also seen for T3, significant tachycardia was observed. No significant change in heart rate or arterial blood pressure was observed for GC-1. In addition to lipid lowering, significant body weight loss was observed for both GC-1 and T3, and the observed weight loss results from modest increases in MVO2 and is not connected to appetite reduction or drug toxicity.
The results from this study suggest the possibility of developing selective thyromimetics for treatment of obesity and hypercholesterolemia. The additional benefit of reducing the risk factor Lp(a) will add a therapeutic dimension not covered by presently available lipid-lowering agents such as HMG-Coenzyme A reductase inhibitors. It is presently unclear whether a 10-fold window separating metabolic rate from tachycardia is adequate for a clinically relevant obesity drug. Therefore, future work to study the physiological factors that govern the relationship between cardiac acceleration and MVO2 in thyroid hormone regulation should be informative. Future studies will include longer durations of treatment in lean as well as obese animal models.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: HDL, High-density lipoprotein; LC/MS, liquid chromatography/mass spectrometry; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); MVO2, oxygen consumption; TR, thyroid hormone receptor.
Received July 30, 2003.
Accepted for publication December 19, 2003.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. EMBO J 17:455–461[CrossRef][Medline]
1-deficient mice is an intrinsic defect. Am J Physiol 275:R640–R646
or ß. Endocrinology 142:544–551This article has been cited by other articles:
 |
|
 |
|
  A. Perra, G. Simbula, M. Simbula, M. Pibiri, M. A. Kowalik, P. Sulas, M. T. Cocco, G. M. Ledda-Columbano, and A. Columbano Thyroid hormone (T3) and TR{beta} agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats FASEB J, August 1, 2008; 22(8): 2981 - 2989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Berkenstam, J. Kristensen, K. Mellstrom, B. Carlsson, J. Malm, S. Rehnmark, N. Garg, C. M. Andersson, M. Rudling, F. Sjoberg, et al. From the Cover: The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans PNAS, January 15, 2008; 105(2): 663 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Grundy Thyroid mimetic as an option for lowering low-density lipoprotein PNAS, January 15, 2008; 105(2): 409 - 410. [Full Text] [PDF]
|
|
|
|
|
|
M. D. Erion, E. E. Cable, B. R. Ito, H. Jiang, J. M. Fujitaki, P. D. Finn, B.-H. Zhang, J. Hou, S. H. Boyer, P. D. van Poelje, et al. From the Cover: Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index PNAS, September 25, 2007; 104(39): 15490 - 15495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Grover, C. Dunn, N.-H. Nguyen, J. Boulet, G. Dong, J. Domogauer, P. Barbounis, and T. S. Scanlan Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 385 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M Villicev, F. R S Freitas, M. S Aoki, C. Taffarel, T. S Scanlan, A. S Moriscot, M. O Ribeiro, A. C Bianco, and C. H A Gouveia Thyroid hormone receptor {beta}-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats J. Endocrinol., April 1, 2007; 193(1): 21 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Flamant, K. Gauthier, and J. Samarut Thyroid Hormones Signaling Is Getting More Complex: STORMs Are Coming Mol. Endocrinol., February 1, 2007; 21(2): 321 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ding, K. Lichti, I. Kim, F. J. Gonzalez, and J. L. Staudinger Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor {alpha}, and the Coactivator Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} J. Biol. Chem., September 8, 2006; 281(36): 26540 - 26551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Columbano, M. Pibiri, M. Deidda, C. Cossu, T. S. Scanlan, G. Chiellini, S. Muntoni, and G. M. Ledda-Columbano The Thyroid Hormone Receptor-{beta} Agonist GC-1 Induces Cell Proliferation in Rat Liver and Pancreas Endocrinology, July 1, 2006; 147(7): 3211 - 3218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Arnold, E. Estebanez-Perpina, M. Togashi, N. Jouravel, A. Shelat, A. C. McReynolds, E. Mar, P. Nguyen, J. D. Baxter, R. J. Fletterick, et al. Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators J. Biol. Chem., December 30, 2005; 280(52): 43048 - 43055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Boelaert and J A Franklyn Thyroid hormone in health and disease J. Endocrinol., October 1, 2005; 187(1): 1 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Prieur, T. Huby, H. Coste, F. G. Schaap, M. J. Chapman, and J. C. Rodriguez Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5 J. Biol. Chem., July 29, 2005; 280(30): 27533 - 27543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Johansson, M. Rudling, T. S. Scanlan, T. Lundasen, P. Webb, J. Baxter, B. Angelin, and P. Parini Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice PNAS, July 19, 2005; 102(29): 10297 - 10302. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
