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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1752-1755
Copyright © 1998 by The Endocrine Society

Original Studies

Increased Oxidizability of Low-Density Lipoproteins in Hypothyroidism

Theo Diekman, Pierre N. M. Demacker, John J. P. Kastelein, Anton F. H. Stalenhoef and Wilmar M. Wiersinga

Departments of Endocrinology (T.D., W.M.W.) and Vascular Medicine (J.J.P.K.), Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam Zuidoost, The Netherlands; and Department of Medicine (P.N.M.D., A.F.H.S.), Division of General Internal Medicine, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Theo Diekman, Department of Endocrinology, University of Amsterdam, F5–171, Meibergdreef 9, Amsterdam Zuidoost, The Netherlands 1105 AZ. E-mail: w.m.wiersinga{at}amc.uva.nl


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hypothyroidism leads to an increase of plasma low-density lipoprotein (LDL) cholesterol levels. Oxidation of LDL particles changes their intrinsic properties, thereby enhancing the development of atherosclerosis. T4 has three specific binding sites on apolipoprotein B; furthermore it inhibits LDL oxidation in vitro. We therefore hypothesized that T4 deficiency not only results in elevated LDL-cholesterol levels but also in increased LDL oxidation.

Ten patients with overt hypothyroidism were studied when untreated (TSH 76 ± 13 mU/L, T4 40 ± 6 nmol/L) and again when they were euthyroid for at least 3 months during T4 treatment (TSH 2.7 ± 0.5 mU/L, T4 115 ± 11 nmol/L). Plasma lipids and lipoproteins and the oxidizability and chemical composition of LDL were determined.

The transition from the hypothyroid to the euthyroid state was associated with a decrease (mean ± SE) of plasma total cholesterol (5.8 ± 0.3 vs. 4.8 ± 0.2 mmol/L, P < 0.005), LDL cholesterol (3.8 ± 0.3 vs. 2.9 ± 0.2 nmol/L, P < 0.005) and apolipoprotein B (1.2 ± 0.1 vs. 0.9 ± 0.1 g/L, P < 0.005); plasma high-density lipoprotein cholesterol, apolipoprotein A-1, and triglycerides did not change. The actual content of dienes in LDL particles was increased in hypothyroidism, with a decrease after T4 suppletion [median (range) = 257 (165–346) vs. 188 (138–254) nmol/mg LDL protein, P < 0.005; reference range 140–180]. The lag time, an estimate of the resistance of LDL against oxidation in vitro, was shortened when hypothyroid but normalized after T4 treatment [29 (19–90) vs. 77 (42–96) min, P < 0.005; reference range 67–87]. The density, the relative fatty acid content, and the vitamin E content of LDL particles did not change.

In conclusion, the hypothyroid state is not only associated with a quantitative increase of LDL particles, but it also changes their quality by increasing LDL oxidizability.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOTHYROIDISM is associated with an increased risk for atherosclerotic vascular disease. Reported major risk factors include dyslipidemia and diastolic hypertension (1). The dyslipidemia is characterized by elevated serum levels of low-density lipoprotein (LDL) cholesterol. Clearance of serum LDL particles is delayed because of a decreased expression of the LDL receptors on liver cell surfaces, which is under the control of T3 (2, 3). One of the key processes in the development of atherosclerosis represents the accumulation of cholesterol by macrophages in the subendothelial space of the vessel wall. Oxidation of LDL particles results in modified LDL, which is no longer recognized by the (apolipoprotein BE) LDL receptor but is taken up by the scavenger receptor on macrophages. Unlike the LDL receptor, the scavenger receptor is not down-regulated with cellular cholesterol accumulation and therefore provides a pathway for the continuous uptake of these chemically modified lipoproteins, which ultimately leads to foam cell formation (4). In an in vitro model, T4 inhibited the oxidation of LDL (5, 6). Apolipoprotein B-100, the protein moiety of LDL, possesses binding sites for T4 (7). Consequently, T4 deficiency could potentially induce a higher susceptibility of LDL for oxidation. To test this hypothesis, we determined the oxidizability of LDL particles in plasma of patients with overt hypothyroidism before and after thyroid hormone replacement.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Ten consecutive patients (5 females, 5 males; mean age 44 yr, range 26–75; with overt hypothyroidism), referred to our outpatient clinic, were studied. The underlying cause of hypothyroidism was Hashimoto’s disease (n = 5); 131I treatment for Graves disease (n = 3); prolonged overdose of thiamazol (n = 1), and subacute thyroiditis (n = 1). None of the patients used any medication known to interfere with lipid metabolism; none used a special diet. The patients were studied before treatment with levothyroxine sodium and again at least three months after achieving the euthyroid state. Overt hypothyroidism was defined as an increased plasma TSH concentration in combination with a decreased plasma free T4 concentration; the euthyroid state was defined as TSH and free T4 levels being within the indicated reference intervals. Blood samples were collected, after an overnight fast, by venipuncture into evacuated tubes containing either EDTA (1 g/L; as an anticoagulant for measurement of lipid profiles and LDL oxidizability) or sodium heparinate (as an anticoagulant for thyroid hormone measurements). After centrifugation (5 min at 3000 x g), 2 mL EDTA plasma samples were collected, to which 20 µL saccharose (600 g/L) was added to stabilize the lipoproteins. Plasma and serum samples were frozen at -80 C until analysis (8). Spontaneous lipid peroxidation may occur in serum samples stored at -20 C. However, when plasma containing EDTA as a metal chelator is stored at -80 C, similar oxidation indices for LDL are found for both fresh plasma samples and those stored for 1 yr (9). The saccharose used as a cryopreservative for LDL has no effect on LDL oxidizability (10). Moreover, the patient specimens were treated in a manner similar to that used for the stored pool of plasma collected from healthy persons used for measuring reference values in our laboratory. This plasma pool has been used now for more than 2 yr, and the parameters of LDL oxidation kinetics have not been changed.

Methods

T4 and T3 were measured by in-house RIA methods (11). Free thyroxine was measured by a two-step fluorescence immuno-assay (DELFIA, Wallac, Turku, Finland); TSH was measured by immunofluorometric assay (DELFIA, Wallac).

Plasma lipid and lipoproteins assay. Total cholesterol in plasma was measured with an enzymatic method (CHOD-PAP, catalog no. 1442350, Boehringer, Almere, The Netherlands) on a Cobas Bio centrifugal analyzer (Roche, Mijdrecht, The Netherlands), high-density lipoprotein cholesterol (after precipitation of very low-density lipoprotein cholesterol and LDL cholesterol with heparin-Mn2+) by the enzymatic CHOD-PAP method, LDL cholesterol was calculated with the Friedewald formula, triglycerides were measured by an enzymatic method (GPO-PAP, catalog no. 701912), and apolipoprotein A-1 and B were assayed with an immunonephelometric method on a Behring nephelometric analyzer (Behring Diagnostics, Rijswijk, The Netherlands), according to the protocol and with reagents of the manufacturer (Behring).

Oxidizability of LDL. Plasma samples of patients were thawed at room temperature, and LDL was isolated by density ultracentrifugation (185,000 x g for 18 h at 4 C) using a swinging bucket Beckman SW40 rotor in a Beckman L55 ultracentrifuge (Beckman, Palo Alto, CA).

After isolation of total LDL, the protein content of LDL was measured by the method of Lowry et al. (12) with chloroform extraction to remove turbidity, using BSA as a standard. The oxidation experiments were performed as described by Esterbauer et al., as modified by Princen et al. (13, 14). Briefly, the oxidation of LDL (60 µg apolipoprotein/mL) was initiated by the addition of CuSO4 to a final concentration of 18 µmol/L, at 37 C. The kinetics of the oxidation of LDL were determined by monitoring the change of the 234-nm diene absorption in a thermostat-controlled ultraviolet spectrophotometer (Lambda 12; Perkin Elmer, Gouda, The Netherlands) equipped with a nine-position automatic sample changer. To minimize the analytical variation absorbance, curves of both LDL preparations from one subject, one before and one during T4 treatment, were analyzed in parallel. The oxidation assay was controlled by analyzing one reference LDL prepared from pooled plasma, stored at -80 C, in every oxidation run. For the reference LDL, the interassay coefficients of variation for lag time, oxidation rate, and the total amount of conjugated dienes formed per milligram of LDL protein were all less than 5%.

From the kinetic absorbance profile of each individual LDL preparation, several indices can be determined that together describe the oxidizability of that particular LDL preparation (see Fig. 1Go). The first index is the initial 234-nm absorbance. With the use of the molar absorbance coefficient for conjugated dienes ({epsilon}234 = 29,500 L·mol-1·cm-1), the initial amount of dienes present in the LDL preparation (expressed as nmol/mg of LDL protein) can be calculated. The second is the lag time (minutes), defined as the interval between the intercept of the linear least-square slope of the curve and the horizontal line through the point of initial-absorbance. Third, the maximal rate of oxidation can be calculated from the slope of the absorbance curve during the propagation phase, expressed as nmol of dienes produced per minute per milligram of LDL protein. By subtracting the initial 234 nm absorbance from the fourth index, the maximal 234-nm absorbance, the total amount of dienes produced (net diene production) can be calculated, expressed as nmol per milligram LDL protein. Finally, the fifth index [t(max)] is the time (in minutes) needed to reach maximal absorbance (that is, to produce the maximal amount of dienes).



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  		Figure 1. Measurement of absorbance at 234 nm during copper-induced in vitro oxidation of LDL, isolated from a patient in the hypothyroid state (+) vs. euthyroid state ({square}). The individual curves show three distinct intervals, which are indicated for the right one as: A, lag time (or initiation phase); B, propagation phase; and C, decomposition phase.

 
Other methods. The concentrations of monounsaturated and polyunsaturated fatty acids in LDL were determined essentially as described by De Graaf et al. (15). Total cholesterol, free (unesterified) cholesterol, phospholipids, and triglycerides in LDL samples were determined by commercially available enzymatic methods (Boehringer-Mannheim, Mannheim, Germany: Nos. 237574, 310328, and 691844; and No. 6639, Sera Pak, Miles, Italy, respectively). The {alpha}-tocopherol (vitamin E) concentrations in LDL were determined by high-performance liquid chromatography, as described previously (15).

Statistical analysis

Statistical evaluation was performed by Student’s t test for paired samples or Wilcoxon matched-pairs signed-rank sum test, when appropriate. A two-tailed probability value less than 0.05 was considered to be a statistically significant difference.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thyroid function tests, lipids, and lipoproteins

The concentrations of plasma TSH, T4, free T4, and T3 all returned to normal values after restoration of the euthyroid state (Table 1Go). As a result of therapy with levothyroxine plasma levels for total cholesterol, LDL cholesterol and apolipoprotein B decreased. Values for high-density lipoprotein cholesterol, apolipoprotein A-1, and triglycerides did not change (Table 1Go).


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  		Table 1. Thyroid function tests and plasma lipid profiles in ten hypothyroid patients before and after treatment with thyroxine

 
LDL oxidizability

Reference intervals for the indices of the oxidation kinetics were determined by measurements in pooled plasma of 12 healthy laboratory workers and are listed in Table 2Go.


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  		Table 2. Oxidation kinetics of LDL isolated from plasma of ten hypothyroid patients before and after treatment with thyroxine

 
In the hypothyroid state, initial dienes, lag time, and T max were all outside the reference interval. The indices for the oxidation kinetics were all clearly (P < 0.01) altered by thyroid hormone substitution (Fig. 1Go and Table 2Go). With correction of the hypothyroid state, lag time increased, and in accordance with this T max. The high initial amount of dienes decreased. Increases within the reference interval were observed in both the oxidation rate and net diene formation.

Chemical composition of LDL

The relative contents for free cholesterol, cholesteryl esters, triglycerides, and phospholipids of LDL particles in the hypothyroid phase and the euthyroid phase were similar (Table 3Go). There was only a minor change in the protein content. The relative changes in fatty acid composition were minimal, with a small increase of the arachidonic acid (20:4) content in the euthyroid state. No change in the vitamin E concentration was observed.


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  		Table 3. Chemical composition, relative fatty acid composition, and vitamin E content of low-density lipoproteins in ten hypothyroid patients before and after treatment with thyroxine

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates that T4 has an important antioxidative effect on LDL in man. Restoration of the euthyroid state changed the plasma LDL particles of hypothyroid patients quantitatively and qualitatively. Quantitatively, the number of LDL particles decreased by 30%, as evident from the decrease in LDL cholesterol and apolipoprotein B and the absence of a change in their chemical composition. The latter excludes the possibility that LDL density changed with consequences for LDL oxidizability. Qualitatively, we observed striking differences in the indices characterizing LDL oxidizability. The lag time of the LDL oxidation curve in vitro increased after adequate thyroid hormone replacement. In the euthyroid state, the lag time did not differ from control values. The lag time of LDL oxidation in vitro is considered to be a function of the content of lipophylic antioxidants present in the LDL particles, mainly {alpha}-tocopherol. Indeed, an increase in lag time is seen during treatment with {alpha}-tocopherol (13, 14, 16). However, on a normal diet, at physiological concentrations of LDL, any correlation between {alpha}-tocopherol content of LDL and lag time is absent (17, 18, 19, 20). This is also true in patients with vitamin E deficiency in whom a high ratio of mono- to polyunsaturated fatty acids (18:1/18:2) of LDL particles seemingly preserved a normal lag time (21). Normalization of lag time, with restoration of the euthyroid state in our hypothyroid patients, was not associated with such favorable changes in the relative fatty acid or vitamin E content.

Next to the decrease in lag time, LDL particles of hypothyroid patients had an increased initial diene concentration. This means that LDL is already peroxidized in the circulation because of the lack of sufficient antioxidant capacity provided by T4. The decrease in the lag time is then a logical consequence because circulating LDL already contains peroxides, which rapidly induce oxidation after adding the Cu2+ ion in the in vitro oxidation test.

Usually, an increase in the lag time is associated with a decreased oxidation rate. This has been observed, e.g. after vitamin E supplementation (13, 14, 16, 21). However, when treated with T4, we observed an increase in both lag time and oxidation rate. We therefore hypothesize that the redox status of T4 is decisive for the presence or absence of lipid peroxidation. During the lag time, T4 is present in the reduced form, and lipid peroxidation can be prevented; once T4 is oxidized at increased oxidative stress, it stimulates lipid peroxidation. The concept of an antioxidant role for T4 is supported by reports in the literature: T4 protects vitamin E-deficient erythrocytes against dialuric acid (5-hydroxy barbituric acid)-induced hemolysis (22) and supranormal levels of thyroid hormones inhibit auto-oxidation of brain homogenates and free-radical mediated oxidation of erythrocyte menbranes (23). It is assumed that LDL oxidation is inhibited in the circulation. However, in the subendothelial layers of the blood vessels, where plasma with excessive amounts of polar antioxidants is absent, the T4 redox state might be an important parameter in determining modification of LDL. T4 deficiency could thus contribute to the well-known, excessive, and uncontrolled cholesterol accumulation in the macrophages, which is the hallmark of atherosclerosis.

Another possible pathophysiological implication of the increase of oxidized LDL in hypothyroidism involves the entry of T4 into cells. Human LDL contains three specific binding sites for T4 localized on apolipoprotein B-100 (7). LDL-T4 complexes are internalized by cell-surface receptors, which decrease in number in hypothyroidism (2). The physiological relevance of the small quantity of T4 attached to LDL is underlined by data that T4 internalization by human fibroblasts is increased about 40% in the presence of LDL when LDL receptors are fully occupied (24). Hypothyroid patients may not benefit from this additional mode of entry of T4 into cells because hypothyroidism causes a reduction in T4 binding to LDL (22), presumably caused by an oxidation-related altered structure of LDL.

Received September 26, 1997.

Accepted January 21, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Klein I. 1990 Thyroid hormone and the cardiovascular system. Am J Med. 88:631–637.[CrossRef][Medline]
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  3. Soutar AK, Knight BL. 1990 Structure and regulation of the LDL receptor and its gene. Br Med Bull. 46:891–916.[Abstract/Free Full Text]
  4. Witzum J. 1994 The oxidation hypothesis of atherosclerosis. Lancet. 344:793–795.[CrossRef][Medline]
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  8. Rumsey SC, Galaneo NF, Arad Y, Deckelbaum RJ. 1992 Cryopreservation with sucrose maintains normal physical and biological properties of human low-density-lipoproteins. J Lipid Res. 33:1551–1561.[Abstract]
  9. Ramos P, Gieseg SP, Schuster B, Esterbauer H. 1995 Effect of temperature and phase transition on oxidation resistance of low-density lipoprotein. J Lipid Res. 36:2113–2118.[Abstract]
  10. Lefèvre G, Myara I, Peynet J, Couderc R, GERBAP Section Lipoprotéins. 1997 Effect of sucrose/-80 C storage of plasma on between-site values of low-density lipoprotein susceptibility to copper-induced oxidation. Clin Chim Acta. 258:249–255.[CrossRef][Medline]
  11. Wiersinga WM, Chopra IJ. 1982 Radioimmunoassays of thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3'-diiodothyronine (T2). Methods Enzymol. 84:272–303.[Medline]
  12. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951 Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–275.[Free Full Text]
  13. Esterbauer H, Striegl G, Puhl H, Rotheneder M. 1989 Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun. 6:67–75.[Medline]
  14. Princen HMG, v Poppel G, Vogelezang C, Buytenhek R, Kok FJ. 1992 Supplementation with vitamin E but not ß-carotene in vivo protects low-density lipoprotein from lipid peroxidation in vitro. Effect of cigarette smoking. Arterioscler Thromb. 12:554–562.[Abstract/Free Full Text]
  15. De Graaf J, Hak-Lemmers HLM, Hectors MPC, Demacker PNM, Hendriks JCM, Stalenhoef AFH. 1991 Enhanced susceptibility to in vitro oxidation of the dense low-density lipoprotein subfraction in healthy subjects. Arteriosclerosis. 11:298–306.[Abstract/Free Full Text]
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  17. Kleinveld HA, Hak-Lemmers HLM, Stalenhoef AFH, Demacker PNM. 1992 Improved measurement of low-density lipoprotein susceptibility to copper-induced oxidation: application of a short procedure for isolating low-density lipoprotein. Clin Chem. 38:2066–2072.[Abstract]
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  21. Kleinveld HA, Naber AHJ, Stalenhoef AFH, Demacker PNM. 1993 Oxidation resistance, oxidation rate, and extent of oxidation of human low-density lipoprotein depend on the ratio of oleic acid to linoleic acid content: studies in vitamin E deficient subjects. Free Radic Biol Med. 15:273–280.[CrossRef][Medline]
  22. Bunyan J, Green J, Edion EE, Diplock AT. 1961 Some antioxidant properties of L-thyroxine in biological systems. Biochim Biophys Acta. 47:403–405.[Medline]
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