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Endocrinology Vol. 149, No. 7 3708-3712
Copyright © 2008 by The Endocrine Society

Reduced Plasma High-Density Lipoprotein Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic Adenosine 5'-Triphosphate-Binding Cassette Transporter 1 Expression

Ivan Tancevski, Andreas Wehinger, Egon Demetz, Philipp Eller, Kristina Duwensee, Julia Huber, Kathrin Hochegger, Wilfried Schgoer, Catherine Fievet, Frans Stellaard, Mats Rudling, Josef R. Patsch and Andreas Ritsch

Department of Internal Medicine (I.T., A.W., E.D., P.E., K.D., J.H., K.H., W.S., J.R.P., A.R.), Innsbruck Medical University, A-6020 Innsbruck, Austria; Institut Pasteur de Lille (C.F.), Département d’Athérosclérose, and Institut National de la Santé et de la Recherche Médicale (C.F.), Unité 545, Lille F-59019, France; Université de Lille 2 (C.F.), Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille F-59006, France; Laboratory of Pediatrics (F.S.), Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9700 Groningen, The Netherlands; and Karolinska Institute at Center for Endocrinology, Metabolism and Diabetes (M.R.), Department of Medicine, Karolinska University Hospital, and Molecular Nutrition Unit, Center for Nutrition and Toxicology, SE-171 77 Stockholm, Sweden

Address all correspondence and requests for reprints to: Ivan Tancevski, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: ivan.tancevski{at}i-med.ac.at.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T3 up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C. The sterol content of bile, liver, and feces was markedly increased, accompanied by up-regulation of hepatic cholesterol 7{alpha}-hydroxylase, and ATP-binding cassette transporter 5, which is known to promote biliary sterol secretion upon dimerization with ATP-binding cassette transporter 8. Both control and hyperthyroid mice exerted identical plasma clearance of iv injected [3H]HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance but, rather, its formation via hepatic ATP-binding cassette transporter 1.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THYROID DISORDERS influence plasma levels of low-density lipoprotein (LDL) cholesterol (LDL-C) and high-density lipoprotein (HDL) cholesterol (HDL-C). Changes in LDL-C have been extensively studied and were attributed to changes in hepatic expression of the LDL receptor (1). However, little is known about the causes of HDL-C decrease under hyperthyroid conditions.

Recently, Parini and colleagues (2) showed that ip treatment of mice with increasing doses of T3 resulted in up-regulation of hepatic scavenger receptor class B, type I (SR-BI), which was accompanied by a reduction of plasma HDL-C. SR-BI, a CD36 family member, mediates high-affinity binding of HDL and the selective uptake of HDL-derived lipids into liver, and represents a physiologically relevant receptor for HDL-C metabolism (3, 4, 5, 6, 7, 8). A further protein expressed in the liver that was shown to influence HDL-C metabolism is ATP-binding cassette transporter 1 (ABCA1) (9). Hepatic ABCA1 is the major transporter that facilitates the efflux of cholesterol to poorly lipidated apolipoprotein (apo) A-I to form nascent or pre-β HDL; in fact, ABCA1-knockout mice are characterized by virtually undetectable plasma HDL-C (10, 11, 12).

In the current study, we describe that induction of severe hyperthyroidism in mice results in a dramatic decrease of plasma HDL-C levels. Our data suggest that in this model of hyperthyroidism, the lowering of plasma HDL-C is due to diminished lipidation via ABCA1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
T3 was purchased from Sigma-Aldrich (St. Louis, MO).

Animals
Male Balb/c mice were obtained from Charles River Laboratories (Kisslegg, Germany), and housed under protocols approved by the Austrian Animal Care and Use Committee. All procedures and care of animals were approved by the Austrian Animal Care and Use Committee. Mice of 20 g were divided into two groups and ip injected with 5 µg T3 in PBS or with PBS alone as a control, respectively (13). Both control and T3-treated mice were under a 12-h light, 12-h dark schedule (lights off at 1900 h), and were injected at 0800 h. After 14-d daily treatment, animals were fasted for 5 h after the last injection and anesthetized. Blood samples were taken, mice were killed by cervical dislocation, and organ biopsies were snap frozen.

Bile and liver cholesterol analysis
The abdominal cavity was opened through a ventral incision. After ligation of the bile ductus and transection of ligamentum falciparum, the gall bladder was removed in toto for exposure. Gall bladder volume was calculated using the formula for ellipsoids: 4/3 x {pi} x a x b2, where a was the longitudinal and b was the cross diameter. Subsequently, bile was aspirated and stored at 4 C. Biliary cholesterol of pooled bile was measured within 14 d using ABX Diagnostics commercial kits (ABX Diagnostics, Montpellier, France). Liver was subdivided into four parts, weighed, and snap frozen. Liver total cholesterol was extracted and measured as described (14).

Hepatic cholesterol synthesis
Hepatic cholesterol synthesis was determined according to a previously described protocol (15). In brief, mice of 20 g were daily injected with T3 for 2 wk as described previously. On d 15, animals received a final T3 injection at 0800 h after an 18-h fasting period. After another 2 h, [1(2)-14C]acetate (100 kBq/animal) was ip injected. Two hours later (4 h after T3 administration), animals were killed and exsanguinated. The abdominal cavity was subsequently opened, and liver specimens were taken, weighed, and snap frozen. Liver cholesterol was extracted as described (15) and [14C]cholesterol measured by liquid scintillation counting.

Lipoprotein parameters
Total cholesterol and triglycerides (TGs) were measured in whole plasma of each animal using ABX Diagnostics commercial kits. In addition, the plasma samples of six animals of each group were combined and subjected to fast protein liquid chromatography fractionation analysis with two tandem Superose 6 columns (GE Healthcare, Vienna, Austria) as described previously (16). apo A-I measurements were performed by an immunonephelometric assay as described (17).

Measurement of phospholipid transfer protein (PLTP) plasma activity
Plasma activity of PLTP was performed as described (16).

[3H]HDL turnover studies
Murine HDL was prepared by ultracentrifugation in the density range of 1.063–1.21 g/ml (18) and radiolabeled with [3H]cholesteryl oleoyl ether (PerkinElmer, Boston, MA) as described (16). Twenty-five micrograms of [3H]HDL were injected into the tail vein of control and hyperthyroid mice, respectively, and blood samples were drawn at 5 min, and 5, 15, and 25 h from the retrobulbar plexus. Plasma samples were analyzed by liquid scintillation counting. The radioactivity of 5 min postinjection is defined as 100% of injected radioactivity.

Fecal sterol analysis
Fifty milligrams of dried feces were boiled in 1 ml alkaline methanol (1 M NaOH/methanol, 1:3 vol/vol) at 80 C for 2 h after addition of 50 nmol 5{alpha}-cholestane as an internal standard for neutral sterol analysis. After cooling down to room temperature, neutral sterols were extracted using three times 3 ml petroleum ether, with a boiling range of 60–80 C. The residual sample was diluted 1:9 with distilled water. One hundred microliters of the solution were subjected to an enzymatic total bile acid measurement (19). The extracted neutral sterols were converted to trimethylsilyl derivatives. Neutral sterol composition of prepared feces samples was determined by capillary gas chromatography on an Agilent gas chromatograph (HP 6890; Agilent Technologies, Inc., Palo Alto, CA) equipped with a 25 m x 0.25 mm CP-Sil-19 fused silica column (Varian, Middelburg, The Netherlands) and a flame ionization detector. The working conditions were the following: injector temperature 280 C; pressure 16.0 {psi} column flow constant at 0.8 ml/min; oven temperature program 240 C (4 min), 10 C/min to 280 C (27 min); detector temperature 300 C.

Plant sterol measurement in plasma
Sitosterol and campesterol were extracted from 10 µl plasma from each animal in duplicate samples. Samples were derivatized with trimethylsilane reagent (pyridine:hexamethyl disilan:trimethylchlorosilane 3:2:1, vol/vol/vol) before gas-chromatography-mass spectrometry analysis (20). D5-campesterol/sitosterol was used as an internal standard. The levels of sitosterol and campesterol in plasma reflect cholesterol absorption (21).

Protein extraction and Western blot analysis
Preparation of hepatic proteins and Western blot analysis were performed as described (16). Immunodetection of SR-BI was performed using a rabbit antibody against SR-BI (NB 400–104; Novus Biologicals, Littleton, CO), and detection of ABCA1 was performed with a polyclonal rabbit anti-ABCA1 antibody (NB 400–105; Novus Biologicals). The chemiluminescent reaction was performed using Super Signal West Dura Reagent (Pierce, Rockford, IL), and blots were visualized by Fluor-S-Imager using Quantity One version 4.1 software (Bio-Rad Laboratories, Inc., Hercules, CA).

RNA isolation, RT, and quantitative real-time PCR
Total RNA was extracted using RNAbee according to the manufacturer’s protocol (Tel-Test, Inc., Friendswood, TX) and reverse transcribed with the Omniscript-RT Kit (QIAGEN, Hilden, Germany). Primers and probes for murine ABCA1, ATP-binding cassette transporter 5 (ABCG5), ATP-binding cassette transporter 8 (ABCG8), and cholesterol 7{alpha}-hydroxylase (CYP7A1) were described previously (22), and primers and probes for murine Niemann-Pick C1 Like 1 protein (NPC1L1) elsewhere (23). GUSB was used as a reference (Applied Biosystems, Foster City, CA). TaqMan real-time PCRs were performed on an Mx4000 Multiplex Quantitative PCR System (Stratagene, Amsterdam, The Netherlands).

Other measurements
Free T3 (fT3) and free T4 (fT4) plasma levels were measured using an immunoassay kit (Roche Diagnostics, Mannheim, Germany). TSH could not be measured because no reliable assay existed at the time these studies were performed.

Statistical analysis
Results are presented as means ± SEM. The statistical significance of the differences between the means of the experimental groups was tested by the Student’s t test for unpaired data. A difference was considered statistically significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To induce severe hyperthyroidism in mice, we used a dosage of T3 described in a previously published study (13). After 14-d treatment, hyperthyroid mice did not show alterations of body weight, when compared with vehicle-treated animals (Table 1Go). Circulating free thyroid hormone (fT3) was increased approximately 5-fold, and fT4 was not detectable in hyperthyroid animals, indicating a negative feedback inhibition of T3/T4 production in the thyroid caused by exogenously administered T3. Plasma total cholesterol in T3-treated mice was decreased by 40%, whereas no significant changes of plasma TGs were observed (Table 1Go). Hyperthyroid animals showed a 40% decrease of HDL-C (Fig. 1AGo) with a concomitant decrease of its major apo, apo A-I (–50%) (Fig. 1BGo), and no significant changes of apo B-containing lipoproteins (Fig. 1AGo).


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  		TABLE 1. Body weight and plasma parameters of control and hyperthyroid mice

 

Figure 1
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  		FIG. 1. Hyperthyroidism lowers plasma HDL-C and promotes excretion of hepatic cholesterol. Chow-fed Balb/c mice were treated with T3 or PBS for 14 d. A, Fast protein liquid chromatography analysis of pooled plasma from control and T3-treated mice (n = 6 per group). B, Immunonephelometric measurement of plasma apo A-I concentration (n = 5–6 per group). C, Representative picture of gall bladders from control and T3-treated animals. D, Enzymatic analysis of hepatic cholesterol concentration (n = 6 per group). E, Hepatic cholesterol de novo synthesis. [14C]Cholesterol (dpm) is normalized to g liver (n = 6 per group). F, Feces were collected for 48 h and analyzed by capillary gas chromatography (n = 5–6 per group). Data presented in percentages are normalized to the respective controls. **, P < 0.01; ***, P < 0.001 vs. corresponding controls. VLDL, Very low-density lipoprotein.

 
Hyperthyroid animals had a 2.7-fold larger gall bladder volume, when compared with controls (52.5 ± 1.9 µl and 19.2 ± 2.2 µl; P < 0.001; n = 3) (Fig. 1CGo), and the cholesterol concentration in gall bladder bile was increased 2.6-fold (Table 1Go). In addition, these animals showed a 40% increase in hepatic cholesterol (Fig. 1DGo). To determine the source of increased hepatic cholesterol, we measured cholesterol de novo synthesis and, indeed, found a 2.5-fold amount of newly synthesized cholesterol in the livers of T3-treated mice (Fig. 1EGo). Analysis of fecal sterol excretion in hyperthyroid mice revealed markedly increased levels of cholesterol as well as of bile acid mass (Fig. 1FGo). Both control and hyperthyroid mice showed identical plasma decay of iv injected [3H]HDL cholesteryl oleoyl ether (Fig. 2Go), thus excluding a different HDL-C clearance. HDL-C concentrations might also be influenced by plasma activity of PLTP, the major lipid transfer protein in the mouse (24). However, we did not observe any differences in PLTP activity between control and hyperthyroid animals (data not shown).


Figure 2
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  		FIG. 2. [3H]HDL turnover study. After 14-d treatment with T3 or PBS, 25 µg [3H]HDL cholesteryl oleoyl ether was injected into the tail vein of control and hyperthyroid mice, respectively, and blood samples were drawn from the retrobulbar plexus at the indicated time points. Plasma samples were analyzed by liquid scintillation counting. The radioactivity of 5 min after injection is defined as 100% of injected radioactivity (n = 4–5). ns, Nonsignificant.

 
Subsequently, we performed Western blot analysis of the two major hepatic proteins involved in HDL metabolism, SR-BI and ABCA1 (3, 25, 26, 27, 28). In agreement with [3H]HDL turnover studies, no significant changes in the hepatic expression of the HDL-receptor SR-BI were observed (Fig. 3AGo). However, ABCA1 was decreased by 40% in the livers of hyperthyroid mice (Fig. 3BGo). Timmins et al. (29) have previously shown that targeted inactivation of hepatic ABCA1 in mice results in an 80% reduction of HDL-C. Thus, ABCA1 was suggested to be responsible for the vast majority of initial lipidation of lipid-poor apo A-I (30).


Figure 3
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  		FIG. 3. Hepatic expression of the major proteins known to influence HDL-C metabolism. Western blot analysis of SR-BI (A) and ABCA1 (B) expression (n = 6 per group). Results are representative of three independent studies. Data presented in percentages are normalized to the respective controls. ***, P < 0.001 vs. corresponding controls. ns, Nonsignificant; T3, treated with T3 for 14 d.

 
Real-time PCR measurements of hyperthyroid liver specimens revealed a transcriptional down-regulation of ABCA1, increased mRNA levels of CYP7A1, the rate-limiting enzyme for conversion of cholesterol into bile acids, and an increased expression of hepatic ATP-binding cassette half-transporter ABCG5, which is known to promote biliary sterol secretion upon dimerization with ABCG8 (ABCG5/G8) (31) (Fig. 4AGo). Yu et al. (31) previously showed overexpression of ABCG5/G8 to enhance biliary cholesterol secretion, to increase neutral sterol loss via the feces, and to reduce strongly the absorption of dietary sterols. Accordingly, induction of hepatic ABCG5/G8 in our hyperthyroid mice was associated with increased biliary cholesterol levels, increased fecal neutral sterol loss, and reduced plasma phytosterol levels (Fig. 4BGo).


Figure 4
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  		FIG. 4. Influence of hyperthyroidism on enterohepatic sterol metabolism. A, TaqMan real-time PCR analysis of hepatic genes involved in cholesterol metabolism (ABCA1, ABCG5, ABCG8) and bile acid synthesis (CYP7A1) (n = 4–10 per group). B, Gas-chromatography-mass spectrometry analysis of diet-derived phytosterols in plasma, normalized to cholesterol. Plasma phytosterol levels reflect intestinal absorption of cholesterol (n = 5 per group). Data are normalized to the respective controls. *, P < 0.05; **, P < 0.01 vs. corresponding controls. T3, Treated with T3 for 14 d.

 
Finally, we investigated the expression of cholesterol transporters within the small intestine of hyperthyroid mice. No significant changes of intestinal ABCG5/G8 and NPC1L1 (32, 33) were found (Fig. 5Go). Interestingly, intestinal expression of ABCA1 was increased 4-fold, which might have attenuated the decrease in plasma HDL-C (34).


Figure 5
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  		FIG. 5. TaqMan real-time PCR analysis of intestinal cholesterol transporters (n = 4–10 per group). Data are normalized to the respective controls. *, P < 0.05 vs. corresponding controls. T3, Treated with T3 for 14 d.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Recent work by Brewer and colleagues (9, 26) indicates that hepatic expression of ABCA1 is crucial for whole body cholesterol homeostasis and, more precisely, for plasma HDL-C levels. Our data suggest that severe hyperthyroidism reduces HDL formation by down-regulating hepatic ABCA1 because the targeted knockdown of hepatic ABCA1 expression has been demonstrated to reduce HDL-C (28, 29). In line with the mentioned studies, we also found a significant decrease of apo A-I plasma levels. However, we cannot exclude that other enzymes involved in lipoprotein metabolism (e.g. lecithin:cholesterol acyltransferase, endothelial lipase, hepatic lipase, or lipid transfer proteins) might play a role in the hyperthyroid scenario. In this study we analyzed PLTP, the major transfer protein in mice, and found no effect of severe hyperthyroidism on its plasma activity. Moreover, severe hyperthyroidism did not influence hepatic SR-BI expression. This finding is in good agreement with data by Johansson et al. (2), suggesting dose-dependent effects of both T3 and a liver-selective thyroid hormone analog on SR-BI expression in the liver of mice.

Because severe hyperthyroidism stimulated hepatic de novo cholesterol synthesis (Fig. 1EGo), which is known to be conferred by the induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase (1), the question arose as to where this excess of cholesterol would be directed. In our experiments, hepatic as well as biliary cholesterol was increased by T3 treatment. Hyperthyroidism also increased fecal cholesterol as well as bile acid mass, and induced hepatic expression of ABCG5 and CYP7A1. These data suggest that increased hepatic production of cholesterol may be counterbalanced by diverting cholesterol from the plasma to the bile, and ultimately to the feces. Increased levels of neutral sterols from the bile, in turn, may compete with cholesterol and plant sterols of dietary origin, thus resulting in decreased intestinal absorption of dietary sterols (35).

The presented study is based exclusively on experiments in mice. Because mice transport the majority of plasma cholesterol as HDL, our data may not be fully applicable to the situation in humans. In the human system, a significant portion of HDL-C is transferred to LDL particles via cholesteryl ester transfer protein. LDL-C, in turn, is cleared by the hepatic LDL receptor. It is known that patients with subclinical hyperthyroidism, or patients treated with TSH-suppressive levothyroxine doses, exhibit a significant reduction in plasma HDL-C levels (1). Accordingly, high doses of thyroid hormone might indeed lead to an overall impaired reverse cholesterol transport. Corresponding experiments in a cholesteryl ester transfer protein-expressing animal, e.g. in rabbits, might help to understand further the role of T3 in lipoprotein metabolism.

From our results in mice, we conclude that severe hyperthyroidism may reduce the formation of nascent HDL particles by a marked down-regulation of hepatic ABCA1. Our results suggest newly synthesized cholesterol to be retained in the liver and to be actively converted into bile salts for biliary excretion and/or to be directly transported into bile, thus increasing the sterol content in the feces of hyperthyroid mice.


   Acknowledgments
 
We thank Professor Hermann Dietrich and his assistants Anton Hanni, Bruno Sailer, and Hermann Hoeller from the Central Laboratory Animal Facilities Innsbruck.


   Footnotes
 
This work was supported by the Hans & Blanca Moser Stiftung (No. 61-1994/95) (to I.T.), the Medizinische Forschungsfoerderung Innsbruck (No. 4316) (to I.T.), the Jubiläumsfond der Oesterreichischen Nationalbank (No. 12156) (to I.T. and A.R.), and the Fonds zur Foerderung der wissenschaftlichen Forschung (P19999-B05) (to A.R.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 3, 2008

Abbreviations: ABCA1, ATP-binding cassette transporter 1; ABCG5, ATP-binding cassette transporter 5; ABCG8, ATP-binding cassette transporter 8; apo, apolipoprotein; CYP7A1, cholesterol 7{alpha}-hydroxylase; fT3, free T3; fT4, free T4; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; NPC1L1, Niemann-Pick C1 Like 1 protein; PLTP, phospholipid transfer protein; SR-BI, scavenger receptor class B, type I; TG, triglyceride.

Received October 15, 2007.

Accepted for publication March 24, 2008.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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