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Endocrine Research Group, Departments of Medicine and Medical Biochemistry, the Faculty of Medicine, University of Calgary, Health Sciences Centre, Calgary, Alberta, Canada, T2N 4N1 (A.H.T., N.C.W.W.), and Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901 (Z.F.S., R.E.S.)
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Summary |
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Summary
Introduction
Materials & Methods
Results & Discussion
References
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Although L-triiodothyronine (L-T3)
lowers cholesterol, this hormone is not used to treat
hypercholesterolemia because of its cardiotoxic effects. Thyromimetics,
such as the novel compound CGS 23425, that mimic the beneficial but
lack the detrimental effects of T3, may be useful in the
treatment of hypercholesterolemia. To show that CGS 23425 has no
cardiotoxicity, atrial contractility and force were both measured and
found to be unchanged in rats treated with up to 10 mg/kg drug. The
lipid lowering actions of this drug resulted in a 44% decrease in
low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats
treated with 10 µg/kg of the compound. Normal rats required a higher
dose of 1000 µg/kg to elicit a similar 50% reduction in LDL
cholesterol. Both CGS 23425 or T3 (10 nM)
increased the specific binding of 125I-labeled LDL to Hep
G2 cells and increased LDL receptor number by 44 and 49%,
respectively. These data indicate that CGS 23425 enhances hepatic
clearance of serum LDL cholesterol. Normal and fat-fed animals treated
with the drug showed a dose-dependent increase in apolipoprotein AI, a
protein that promotes the efflux of cholesterol from peripheral
tissues. Transient transfection of a rat apolipoprotein AI
promoter-chloramphenicol acetyltransferase construct, in human hepatoma
cells, showed a dose-dependent increase in chloramphenicol
acetyltransferase activity with EC50 values of 2 × 10-12 M and 10-10 M for
thyroid hormone receptors 
1 and 
1, respectively, with maximal
responses at 10-7 M. These data indicate that
CGS 23425 is a thyromimetic that increases apolipoprotein AI expression
via thyroid hormone receptor. In summary, CGS 23425 ameliorates
hypercholesterolemia by increasing apolipoprotein A1 and the clearance
of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful
for the prevention and reversal of atherosclerosis.
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Introduction |
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Summary
Introduction
Materials & Methods
Results & Discussion
References
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The administration of thyroid hormones or related analogs lowers plasma cholesterol in hypothyroid patients (1, 2). This beneficial effect of the thyroid hormones (L-T3 and L-T4) and thyromimetics arises from their actions on nuclear receptors for L-T3. The liganded receptors regulate the expression of several hepatic genes involved in cholesterol metabolism. For example, L-T3 increases the expression of LDL receptors and several lipolytic enzymes (2-6). Unfortunately, the natural thyroid hormones cannot be used therapeutically to treat hypercholesterolemia, in euthyroid individuals, because of their undesirable effects on the heart (7). However, synthetic thyromimetics designed specifically to eliminate or reduce the cardiac side effects and target one of the major sites of cholesterol metabolism, the liver, are expected to have a therapeutic role. Selective actions of thyromimetics on the liver may in theory arise from differences in (i) cytoplasmic binding, (ii) active transport at the plasma membrane, (iii) the activities of a putative stereospecific cytoplasm-to-nucleus transport system and/or (iv) differential binding to the two major isoforms of nuclear T3 receptor in hepatocytes compared with other cell types (8-10). Hepatic selective thyromimetics are therefore designed to exploit one or more of these parameters.
In this report, we describe a novel thyromimetic that lowers plasma cholesterol by 60% at doses that have no effect on the heart. The reduction in plasma cholesterol is mediated by an increase in hepatic LDL receptor activity. In addition, this thyromimetic increases plasma apoAI concentrations, the major apoprotein constituent of HDL particles that have antiatherogenic properties. We anticipate that a thyromimetic such as CGS 23425 will eventually be useful in the medical treatment of hypercholesterolemia.
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Materials and Methods |
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Summary
Introduction
Materials & Methods
Results & Discussion
References
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Animals. Male Sprague-Dawley rats, weighing between 150 and 200 g, were maintained on a normal rat chow diet (chow-fed) or a chow diet supplemented with 1.5% cholesterol and 0.5% cholic acid (fat-fed) for 14 days before experiments. Groups of six chow- or fat-fed rats were treated orally by gavage with a solution of CGS 23425 or vehicle (water) orally in the doses indicated for 7 consecutive days. After the last dose, the animals were fasted for 18 hr before being killed, and blood was collected for studies outlined below.
Preparation of hepatic plasma membranes and nuclei.
Livers
from euthyroid male Sprague-Dawley rats were dissected free of adhering
membranes and large blood vessels. Nuclei from homogenized-filtered
livers were isolated by differential centrifugation (11) and the
supernatant-containing plasma membranes collected. The
nuclei-containing pellet was resuspended in buffer A [20
mM Tris·HCl, 0.25 M sucrose, 1 mM
MgCl2O·6H2O, 2 mM EDTA, 0.1 mM NaCl, 5% glycerol, pH 7.2]
and recentrifuged. The nuclei were dissolved in 180 µl of buffer A
(12) and stored at 
40°.
Competitive binding assay of [125I]T3 to hepatic nuclei and plasma membranes. Nuclear binding was performed according to Stephan et al. (13). Briefly, 300 µg of protein were incubated with 0.3 nM [125I]T3 (1080 mCi/mg; DuPont-New England Nuclear, Boston, MA) for 50 min at 22° in a final volume of 1 ml of buffer A. Parallel incubations contained increasing concentrations of L-T3 (Sigma, St. Louis, MO), CGS 23425 (Novartis, Summit, NJ), CGS 26214 (Novartis), D-T4 (Sigma), or SKF-94901 (SmithKline French). Nonspecific binding was determined in the presence of 3 µM unlabeled L-T3.
Plasma membrane binding was determined using Pliam and Goldfine's (14) method. Briefly, 90 mg of membrane protein were incubated with 0.2 nM [125I]T3 for 30 min at room temperature. Parallel incubations contained increasing concentrations of L-T3 or the indicated thyromimetics. Nonspecific binding was determined in the presence of 6 µM unlabeled L-T3. In both studies, bound and free radioactivities were separated by centrifugation, and radioactivity in the pellet was measured by
-counting. The concentration of the test
compounds corresponding to IC50 of specific
binding of [125I]T3 was
determined from the reciprocal plots of specific binding versus
concentration of test compounds.
Serum lipoprotein determinations. Chow- or fat-fed euthyroid male Sprague-Dawley rats were treated with increasing concentrations of CGS 23425 for 7 days. Animals were fasted for 18 hr after the last dosing, and blood was collected by cardiac puncture under CO2 anesthesia into EDTA (5%). Plasma was prepared by centrifugation, and samples were analyzed enzymatically for total, HDL cholesterol, and LDL cholesterol on a Bio-Mek automated workstation (Beckman Instruments, Palo Alto, CA) using Sigma diagnostic reagent kits. Plasma apoAI concentrations were measured using Western blot analysis and electrochemiluminescence detection as described previously (15).
Effect of CGS 23425 on the heart. Animals on a normal diet were treated with up to 40 mg/kg CGS 23425 for 7 days. The animals were weighed, and the hearts were dissected free from euthanized animals. The weight of the hearts were rapidly measured and placed in oxygenated Kreb's buffer at 28°. The right atria were isolated by dissection, hung with minimum applied tension, and allowed to equilibrate for 30 min. The spontaneous atrial rate was then determined. The left atria were isolated and used to measure maximum stimulated contractile atrial force, by creation of tension-force curves. Briefly, atria were attached to platinum electrodes in Kreb's buffer, and a resting tension of 2 g was applied. Cardiac muscle was then stimulated at 10 beats/min with a 2.5-msec duration and then allowed to equilibrate for 30 min (initial force). Tension-force curves using isometric contractile forces of 10-60 beats/min were constructed, and the maximum contractile force was measured (16).
Determination of rat apo AI promoter activity.
Human fetal
hepatoma cells (HuH-7 cells) were maintained in RPMI-ISE medium as
previously described (17). Cells were transfected via the calcium
phosphate co-precipitation method, with 2.5 µg of pAI.474.CAT (17)
together with 5 µg of either pECE-hTR or pECE-hTR and 2.5 µg
of the bacterial plasmid pRSV--galactosidase, to monitor DNA uptake
(17). After 24 hr of incubation, the medium was exchanged for one
containing different concentrations of CGS 23425 or
L-T3. After a further 24 hr of
incubation, transfected cells were harvested, and cellular protein was
assayed for -galactosidase and CAT activity as described elsewhere
(17). EC50 values were determined directly from
the graphs.
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Results and Discussion |
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Summary
Introduction
Materials & Methods
Results & Discussion
References
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Comparison of CGS 23425 with other thyromimetics. To compare the thyromimetic properties of various compounds, we tested their ability to compete with the binding of [125I]T3 in vitro to rat liver nuclei and plasma membranes (Table 1). Competition with [125I]T3 in binding to nuclei demonstrates the thyromimetic property of the compound under investigation, and competition with [125I]T3 in binding to rat liver plasma membranes indicates its stereospecificity (14). The latter feature is of interest because several cardiac effects of L-T3 are correlated with its ability to interact directly with the plasma membrane (18). To design a thyromimetic with low toxicity we sought compounds devoid of hepatic plasma membrane binding.
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Effect of CGS 23425 on the heart. To determine the effects of CGS 23425 on the heart, the compound was administered to normal euthyroid male rats in doses up to 40 mg/kg/day. There was no difference in the body weight and in vivo heart rate of control animals [(mean ± standard error) 295 ± 10 g, 404 ± 19 beats/min] compared with those treated (301 ± 14 g, 410 ± 14 beats/min) with 40 mg/kg/day. Myocardial activity, measured as heart rate of isolated atria, was reduced by 21% to 150 beats/min but only at the highest dose tested (Table 2). Additionally, there was a concomitant increase in the measured atrial force of 17%. Enhanced myocardial contractile force is accompanied by cardiac hypertrophy (20), and therefore, the observed 19% increase in total heart weight was not unexpected. At lower doses of 2.5, 10, and 20 mg/kg/day, CGS 23425 had no effect on these parameters. Together these data indicate that the compound does not appear to have cardiotoxic effects at low doses, but at the highest dose of 40 mg/kg/day, the undesirable effects on the heart begin to appear. These data are similar to those for CGS 26214 and SKF 94901. Neither of these thyromimetics has a cardiotoxic effect at doses up to 25 mg/kg and 1.8 × 10-5 mol/kg/dl (~100 mg/kg), respectively (21, 22). Doses of L-T3 as low as 10 µg/kg, by comparison, showed significant cardiotoxicity in similarly treated animals (13).
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Hypocholesterolemic effects of CGS 23425. Although the preceding results show that low doses of CGS 23425 had no significant effect on the heart, whether this compound lowered cholesterol levels remained unknown. To demonstrate clearly a beneficial hypocholesterolemic effect of CGS 23425, male rats fed a diet supplemented with cholic acid and cholesterol were used, because such animals show elevated levels of serum cholesterol (23). Results showed that the drug was effective at a minimum dose of 10 µg/kg/day and reduced total cholesterol levels by 60% of the untreated controls (118 ± 15 mg/dl compared with 190 ± 21 mg/dl; Fig. 1, bottom). Doses that exceeded 10 µg/kg/day showed no further reduction in cholesterol levels. Although male rats fed a standard diet and treated in the same manner showed a 10% decrease in serum cholesterol, they required a higher dose (1000 µg/kg/day) of CGS 23425 (Fig. 1), but this was not significantly different (p = 0.06) from chow-fed rats. This lack of effect of thyroid hormones and thyromimetics on serum cholesterol in rats fed a standard diet has been thoroughly documented (24).
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CGS 23425 lowers LDL cholesterol. The observed reduction in serum cholesterol may arise from changes in either the concentration of LDL or HDL. LDL particles participate in the shuttling of cholesterol from the liver to steroidogenic target tissues, whereas HDL, a key component of "reverse" cholesterol transport, does the opposite and removes cholesterol from peripheral tissues and returns it to the liver (25). Hypercholesterolemic patients would benefit from a reduction in the level of LDL with an increased abundance of HDL (26).
Because thyromimetics decrease LDL cholesterol by enhancing the clearance of these particles through increased hepatic LDL receptor number (27, 28), we asked if CGS 23425 could increase hepatic LDL receptor number and reduce serum LDL concentrations. Therefore, fractionated sera were analyzed for LDL cholesterol content using an enzymatic assay (Fig. 1, LDL). Results showed that LDL was significantly reduced in both fat- and chow-fed rats at the minimum effective dose. In fat-fed rats, there was a 44% reduction in LDL cholesterol at 10 µg/kg/day, and the chow-fed rats showed a 50% reduction at 1000 µg/kg/day (Fig. 1). The pattern of LDL reduction in the fat-fed rats mirrored exactly that of total cholesterol (Fig. 1, bottom), suggesting cholesterol reduction in these animals is primarily through receptor-mediated removal of LDL cholesterol at the liver. The lack of a hypocholesterolemic effect of low dose CGS 23425 in the chow-fed rats may arise from low levels of LDL cholesterol in the sera and/or the already high level of LDL receptor activity in these animals. Additionally, normocholesterolemic rats tend to transport cholesterol on HDL rather than on LDL particles and are less responsive to L-T3 treatment (29), and this may account for a lack of effect of CGS 23425 in the chow-fed rats. To test the hypothesis that CGS 23425 might increase LDL receptor number, we measured the binding of 125I-LDL to HepG2 cells treated with 10 nM of the compound. Results showed a 44% increase in LDL receptor number from 81 ± 4 to 117 ± 9 ng/mg of protein (mean ± standard error; n = 6). This value is comparable to a 49% increase in LDL receptor number induced by 10 nM L-T3 (81 ± 4 to 121 ± 9 ng/mg protein). These observations suggest that CGS 23425 exerts a major effect on cholesterol metabolism via its ability to enhance LDL particle removal. These data are similar to those obtained from studies with CGS 26214 (21) and SKF 94901 (30), in which serum cholesterol concentrations were reduced via increased LDL clearance.Effect of CGS 23425 on HDL. Raising HDL in hyper- and normocholesterolemic individuals is of significant benefit in the prevention of accelerated atherosclerosis (26). Therefore, the HDL levels in the sera of these animals were measured in response to the drug. In CGS 23425-treated fat-fed rats, we observed a small but significant increase in HDL levels at 100 µg/kg/day (Fig. 1, HDL), whereas chow-fed rats showed no change in their HDL. These data suggest that CGS 23425 has a minimal effect on the abundance of HDL. Nevertheless, the single point showing significant elevation of HDL at 100 µg/kg/day and the known induction of apoAI protein by L-T3 prompted us to measure serum levels of this protein. The finding of elevated levels of apoAI alone is important because of its cardioprotective effect in preventing accelerated atherosclerosis (31).
Serum apoAI protein concentrations increased in a dose-dependent manner in both experimental groups (Fig. 1, top). In fat-fed rats, there was a 2.4- and 5.7-fold increase in the levels of apoAI at 30 and 300 µg/kg/day, respectively. The rats on a standard chow diet also showed a significant 1.3- and 1.7-fold increase in apoAI at 100 and 1000 µg/kg/day, respectively (Fig. 1). Why CGS 23425 increases the apoAI level without marked changes in the HDL is uncertain; but because there is evidence to suggest that apoAI is a cholesterol acceptor molecule when separated from HDL, and an independent activator of lecithin:cholesterylacetyl transferase (25), then the actions of the compound on apoAI may prove to be an added benefit in the thyromimetic action of CGS 23425. Although we (17) and others (32) have previously shown L-T3 to significantly induce apoAI expression in rats, there are no comparable human data. However, there is circumstantial evidence from genetic linkage analysis that suggests that L-T3 is closely associated with apoAI and HDL expression in man (33). This would suggest that CGS 23425 would have a beneficial effect on human apoAI expression, HDL concentration, and HDL:LDL ratios.Differential effects of CGS 23425 on TR isoform activity.
The
results of the preceding studies show that CGS 23425 increased rat
apoAI abundance in a fashion similar to that of
L-T3 (17). To determine whether the
increase was due to enhanced gene transcription, we measured the
activity of the rat apoAI promoter in transient transfection assays
using human fetal hepatoma (HuH-7) cells (17). HuH-7 cells were used
for these studies because they readily respond to
L-T3 (17) and are not exposed to the
hormones found in serum. CGS 23425 caused a dose-dependent increase in
apoAI promoter activity with a maximal 5-fold increase (Fig.
2). However, the two major isoforms of
thyroid hormone receptor, TR1 and TR1, responded differently to
this thyromimetic (Fig. 2). Although both reached a maximal 5-fold
increase in apoAI promoter activity, the concentration required for
half-maximal stimulation (EC50) was lower in the
presence of TR1. The EC50 for TR1 was ~2 × 10-12 M, and for TR1
it was ~10-10 M (Fig. 2). In
comparison, L-T3 in the same assay
system produced dose-dependent curves for both isoforms of the receptor
that overlapped with EC50 values of 6 × 10-11 M. Additionally, the maximum
response to T3 was only 3-fold. This apparent
increase in apoAI promoter response is similar to that seen with TRIAC
(34), where TRIAC produces increased promoter activity compared with
L-T3 and a differential effect on
TR and TR receptors. These changes probably reflect increased
receptor occupancy compared with
L-T3. This conclusion is supported by the nuclear binding data that showed higher binding affinities for CGS
23425 to intact hepatic nuclei (Table 1). Additionally, TRIAC has also
been shown to have higher affinity for TR receptors compared with
TR receptors (34). Another thyromimetic analog, 3,5,3
-triiodothyropropionic acid shows similar differential isoform activation effects (34), but does not produce a transcriptional response. The hepatic selectivity and lack of cardiac toxicity exhibited by CGS 23425 may be due to its differential effects on the
two major isoforms of TR. This possibility is supported by the fact
that the predominant TR isoform in the liver is TR1 and in the heart
is TR1 (35, 36).
|
1 and TR1 provides a useful tool for dissecting the
actions of these receptors in response to ligand. A compound such as
CGS 23425 may prove to be useful in the treatment of
hypercholesterolemia.
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Footnotes |
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Received March 10, 1997; Accepted May 15, 1997
Funding for a portion of this project was provided by the Medical Research Council of Canada and the Heart and Stroke Foundation of Canada. N.C.W.W. is a recipient of a Senior Scholarship Award from the Alberta Heritage Foundation for Medical Research and a Scientist Award from the Medical Research Council.
Send reprint requests to: Dr. N. C. W. Wong, University of Calgary, Depts. of Medicine and Medical Biochemistry, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1 Canada. E-mail: ncwwong{at}acs.ucalgary.ca
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Abbreviations |
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T3, triiodothyronine; T4, thyroxine; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CAT, chloramphenicol acetyltransferase; apoAI, apolipoprotein AI; TR, thyroid hormone receptor; TRIAC, triiodothyroacetic acid.
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References |
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Summary
Introduction
Materials & Methods
Results & Discussion
References
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P. M. Yen Thyroid hormones and 3,5-diiodothyropropionic Acid: new keys for new locks. Endocrinology, April 1, 2006; 147(4): 1598 - 1601. [Full Text] [PDF]
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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]
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L. E. Macdonald, K. E. Wortley, L. C. Gowen, K. D. Anderson, J. D. Murray, W. T. Poueymirou, M. V. Simmons, D. Barber, D. M. Valenzuela, A. N. Economides, et al. Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5 PNAS, February 15, 2005; 102(7): 2496 - 2501. [Abstract] [Full Text] [PDF]
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S. Borngraeber, M.-J. Budny, G. Chiellini, S. T. Cunha-Lima, M. Togashi, P. Webb, J. D. Baxter, T. S. Scanlan, and R. J. Fletterick Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor PNAS, December 23, 2003; 100(26): 15358 - 15363. [Abstract] [Full Text] [PDF]
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S. U. Trost, E. Swanson, B. Gloss, D. B. Wang-Iverson, H. Zhang, T. Volodarsky, G. J. Grover, J. D. Baxter, G. Chiellini, T. S. Scanlan, et al. The Thyroid Hormone Receptor-{beta}-Selective Agonist GC-1 Differentially Affects Plasma Lipids and Cardiac Activity Endocrinology, September 1, 2000; 141(9): 3057 - 3064. [Abstract] [Full Text] [PDF]
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G. Thomas, F. Bertrand, and B. Saunier The Differential Regulation of Group IIA and Group V Low Molecular Weight Phospholipases A2 in Cultured Rat Astrocytes J. Biol. Chem., April 6, 2000; 275(15): 10876 - 10886. [Abstract] [Full Text] [PDF]
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