Thyroid Hormone Reduces Cholesterol via a Non-LDL Receptor-Mediated Pathway

Endocrinology, Nov 2012

Although studies in vitro and in hypothyroid animals show that thyroid hormone can, under some circumstances, modulate the actions of low-density lipoprotein (LDL) receptors, the mechanisms responsible for thyroid hormone's lipid-lowering effects are not completely understood. We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T3 and 3,5-diiodo-l-thyronine. High doses of both 3,5-diiodo-l-thyronine and T3 dramatically reduced circulating total and very low-density lipoprotein/LDL cholesterol (∼70%) and were associated with reduced plasma T4 level. The cholesterol reduction was especially evident in the LDLR-knockout mice. Circulating levels of both apolipoprotein B (apo)B48 and apoB100 were decreased. Surprisingly, this reduction was not associated with increased protein or mRNA expression of the hepatic lipoprotein receptors LDLR-related protein 1 or scavenger receptor-B1. Liver production of apoB was markedly reduced, whereas triglyceride production was increased. Thus, thyroid hormones reduce apoB lipoproteins via a non-LDLR pathway that leads to decreased liver apoB production. This suggests that drugs that operate in a similar manner could be a new therapy for patients with genetic defects in the LDLR.

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Thyroid Hormone Reduces Cholesterol via a Non-LDL Receptor-Mediated Pathway

Received May Thyroid Hormone Reduces Cholesterol via a Non-LDL Receptor-Mediated Pathway Ira J. Goldberg 0 Li-Shin Huang 0 Lesley A. Huggins 0 Shuiqing Yu 0 Prabhakara R. Nagareddy 0 Thomas S. Scanlan 0 Joel R. Ehrenkranz 0 0 Department of Medicine (I.J.G., L.-S.H., L.A.H., S.Y., P.R.N.) , Columbia University , New York , New York 10032; Departments of Physiology and Pharmacology (T.S.C.), Oregon Health and Science University , Portland, Oregon 97239; and Department of Medicine (J.R.E.), Intermountain Healthcare and University of Utah School of Medicine , Salt Lake City, Utah 84132 , USA Although studies in vitro and in hypothyroid animals show that thyroid hormone can, under some circumstances, modulate the actions of low-density lipoprotein (LDL) receptors, the mechanisms responsible for thyroid hormone's lipid-lowering effects are not completely understood. We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T3 and 3,5-diiodo-L-thyronine. High doses of both 3,5-diiodo-L-thyronine and T3 dramatically reduced circulating total and very lowdensity lipoprotein/LDL cholesterol ( 70%) and were associated with reduced plasma T4 level. The cholesterol reduction was especially evident in the LDLR-knockout mice. Circulating levels of both apolipoprotein B (apo)B48 and apoB100 were decreased. Surprisingly, this reduction was not associated with increased protein or mRNA expression of the hepatic lipoprotein receptors LDLRrelated protein 1 or scavenger receptor-B1. Liver production of apoB was markedly reduced, whereas triglyceride production was increased. Thus, thyroid hormones reduce apoB lipoproteins via a non-LDLR pathway that leads to decreased liver apoB production. This suggests that drugs that operate in a similar manner could be a new therapy for patients with genetic defects in the LDLR. (Endocrinology 153: 5143-5149, 2012) - Tlating cholesterol levels, first documented in experihe mechanism for thyroid hormones? effects on circumental animal and human studies between 1923 and 1930 ( 1 ), is not completely understood. The principal thyroid hormone in the circulation is T4, which is deiodinated to its active metabolite T3. The effects of T4 and T3 on cholesterol levels are thought to occur via nuclear thyroid hormone receptors (TR), in particular hepatic TR- ( 2 ). 3,5-Diiodo-L-thyronine (T2) is an endogenous thyroid hormone that is readily detectable ( 100 pmol/liter) in the circulation ( 3 ) and lowers plasma cholesterol concentrations in humans ( 4 ). T2 is thought to be a less avid ligand for nuclear thyroid receptors. Experiments in animals show that T2 acts through an extranuclear, nongenomic mechanism ( 5 ). Although the standard teaching is that thyroid hormone excess leads to an increase in low-density lipoprotein (LDL) receptors (LDLR) ( 6, 7 ), and that thyroid deficiency decreases LDLR due to a reduction in sterol-regulatory element binding protein 2 (8), in vivo data supporting this mechanism of action are limited. The mechanism by which T2 lowers circulating cholesterol levels is not known. Use of thyroid hormone for the treatment of hyperlipidemia is limited by thyrotoxic side-effects that occur when T4 or T3 is administered to lower cholesterol; this was illustrated in the Coronary Drug Project that used d-T4 ( 9 ). To avoid this complication, thyroid hormone analogs, thyromimetics, which preferentially interact with hepatic TR- receptors to lower cholesterol levels, have been developed ( 10 ). Two recent studies on the lipid-lowering effects of thyromimetics showed an induction of scavenger receptor-B1 (SR-B1) with no changes in LDLR Abbreviations: apoB, Apolipoprotein B; HDL, high-density lipoprotein; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; LDLR, LDL receptor; LRP, LDL receptorrelated protein; T2 , 3,5-diiodo-L-thyronine; TR, thyroid hormone receptor; VLDL, very low density lipoprotein; WT, wild type; WTD, Western-type diet. endo.endojournals.org ( 11, 12 ). Up-regulation of SR-B1 would explain the reduction in high-density lipoprotein (HDL) sometimes seen with thyroid hormone administration and could lead to increased reverse cholesterol transport (12). One study recently reported that the thyromimetic T-0681 does not alter expression of the LDLR in wild-type (WT) mice, an effect that implies a mechanism of action other than via LDLR. Surprisingly, T-0681 treatment failed to reduce cholesterol in LDLR-knockout (Ldlr / ) mice ( 12 ), suggesting that LDLR were essential for the cholesterol-decreasing actions of this drug. The goal of the following study was to determine whether thyroid hormone affects cholesterol levels exclusive of effects on the LDLR. Materials and Methods Mice and thyroid hormone treatments All studies were approved by the Columbia University Institutional Animal Care and Use Committee. WT C57BL/6 and Ldlr / mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Male mice (3- to 4 months of age) were maintained on chow diets and allowed to eat and drink ad libitum. At the initiation of the study they were switched to a Western-type diet (WTD) containing 42% fat, 42.7% carbohydrate, 15.2% protein, 0.15% cholesterol; total 4.5kcal/g (Harlan Teklad, Madison, WI). After 1 wk, the animals were divided into groups receiving vehicle (58.5% saline 40% dimethylsulfoxide 1.5% 1 M NaOH) or thyroid hormones-T3 (7.5?750 g/kg) [EMD Chemicals (Philadelphia, PA)/Calbiochem)] or T2 (1.25 mg/kg or 12.5 mg/kg) (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) via daily gavage for another week. Mass spectrometry and nuclear magnetic resonance profiles showed no T3 or T4 contamination in the T2. Mice were killed or used for kinetic studies at the end of thyroid hormone treatment. All blood samples were collected in 4-h fasted mice. Blood glucose was obtained from a tail prick using a glucometer. For other assays, blood samples were drawn via retro-orbital plexus in anesthetized mice. Plasma lipid, T4, and apolipoprotein B (apoB) measurements Plasma levels of triglyceride, free fatty acids. and cholesterol were measured using the following kits: Infinity Triglyceride Reagent (Fisher Scientific, Pittsburgh, PA), Infinity Total Cholesterol Reagent (Fisher), NEFA-HR (WAKO Chemicals USA, Inc., Richmond, VA). Because total plasma cholesterol in WT mice is predominantly derived from HDL, plasma lipoproteins were isolated by ultracentrifugation (TLA100 rotor, Beckman Instruments, Fullerton, CA). Cholesterol and triglyceride in very low density lipoprotein (VLDL) (d 1.006 g/ml), intermediate density lipoprotein (IDL)/LDL (d 1.006 ?1.063 g/ml), and HDL (d 1.063?1.21 g/ml) fractions were measured as described above. Circulating T4 was measured using Mouse/Rat T4 Total kit (Calbiotech, San Diego, CA). Plasma apoB100 and B48 in the plasma (1 l) were separated in 4% SDS-PAGE, stained with Coomassie blue. and quantitated by densitometry. Liver expression of lipoprotein receptors and other metabolic genes At the conclusion of each study, liver was collected. Livers were homogenized in a RIPA buffer from Pierce Chemical Co. (Rockford, IL) (50 mM Tris-HCl, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulfate) and protease inhibitors. Homogenates (20 g/sample) were used for Western blot analysis using the following antibodies against mouse proteins: anti-LDLR and anti-LDLR-related protein (LRP) 1 (Abcam, Cambridge, MA), anti-SR-BI (Novus Biologicals, Littleton, CO), and anti-glyceraldehyde 3-phosphate dehydrogenase (Cell Signaling Technology, Danvers, MA). Hepatic mRNA levels were assessed by real time PCR. Primers for each gene are included in Supplemental Table 1 published on The Endocrine Society?s Journals Online web site at http://endo.endojournals.org. Triglyceride and apoB production Liver production of lipoproteins was assessed in 4-h fasted mice injected with [35S]methionine (200 Ci/mouse; PerkinElmer, Wellesley, MA) and Triton WR 1339 (500 mg/kg; Sigma Chemical Co., St. Louis, MO), as described previously ( 13 ). Labeled apoB was assessed directly from plasma by 4% SDS-PAGE and quantified by densitometric scanning of x-ray film and normalized to trichoroacetic acid-precipitable counts as previously described ( 14 ). Statistical analysis Comparisons between two treatment groups were performed using Student?s t test. Comparisons among three or more groups were performed using one-way ANOVA. Data are given as mean SEM. Results Plasma cholesterol reduction in Ldlr / mice treated with T3 and T2 T3 and T2 treatments caused a marked reduction in total cholesterol (Table 1). Feeding control mice with a WTD led to a marked increase in cholesterol from 160 to 1336 mg/dl. Treatment with T3 (0.75 mg/kg) had a dramatic effect on circulating cholesterol, which was reduced approximately 70% to 406 mg/dl. Triglyceride levels, in contrast, were similar in control and T3-treated animals. Circulating glucose was substantially reduced from 160 to 77 mg/dl. Body weight was not affected by this short-term T3 treatment. Heart weights were increased, whereas adipose, muscle, and liver weights were not significantly altered (Supplemental Table 2). We also performed a doseresponse curve in Ldlr / mice using decreasing doses of T3. Even at 7.5 g/kg the mice had a marked reduction in cholesterol (Supplemental Table 3). We then assessed the effects of T2 on these mice. The dose of T2 used in these experiments was extrapolated from par Cholesterol (mg/dl) Triglyceride (mg/dl) Glucose (mg/dl) Body Weight (g) Cholesterol (mg/dl) Triglyceride (mg/dl) Glucose (mg/dl) Body Weight (g) Cholesterol (mg/dl) Triglyceride (mg/dl) Glucose (mg/dl) Body weight (g) T4 ( g/dl) Age-matched male Ldlr / or WT C57BL/6 mice on a chow diet were bled for baseline blood biochemistry. Mice were switched to a WTD for 1 wk and then bled for blood biochemistry (i.e. 1 wk WTD). These mice were continued on WTD with an addition of daily oral gavage of thyroid bhoPrmo0n.e01(T; Hc)Pat in0d.0ic0a1t.edNudmosbeesrfoofr mT3icoer iTn2e,aocrhogfrvoeuhpiclies gcoivnetnroinl(pCaorne)nftohresains.other week (i.e. 1 wk TH treatment). P values (vs. Con): a P 0.05; enteral doses that improve insulin sensitivity and reduce chodose) led to a similar cholesterol reduction of approxilesterol in rats ( 15 ). Therefore, we used two higher doses that mately 70% and reduced glucose. were given orally. Similar to what was found for T3, cholesterol was reduced ( 70%) with the higher dose, triglycerides were unchanged, and glucose was reduced (Table 1). These effects were dose dependent, because lower dose T2 also reduced cholesterol levels (by 28%), did not change triglyceride or glucose levels, and had a less pronounced effect on heart weight (Supplemental Table 2). The effects of T3 and T2 were also assessed in WTD-fed WT C57BL/6 mice (Table 1). Both T3 and T2 (12.5 mg/kg To determine whether T2 at these doses worked by a mechanism that did not alter pituitary function, we measured circulating T4. Both T3 and T2 (12.5 mg/kg dose) treatments led to a marked suppression of circulating T 4 levels, indicating suppression of the pituitary axis. Changes in lipoprotein fractions Lipoproteins are shown in Table 2. In all mice the reductions in cholesterol were due to decreases in VLDL and A. Ldlr / Lipoproteins 1.25 mg/kg 12.5 mg/kg Con B48 Con T2 T3 * B B100 B48 )U 2.5x105 A ( oB 2.0x105 p A ed 1.5x105 t e r ce 1.0x105 S y lew 5.0x104 N D LDLR GAPDH 0 60 120 Time (min) FIG. 1. Plasma apoB distribution, apoB, triglyceride production in Ldlr / mice and Western blot analysis of LDLR in WT mice. A, Fasting plasma apoB100 and B48. Plasma (1 l) proteins from Ldlr / mice were separated in 4% SDS-PAGE and stained with Coomassie blue. Representative samples are shown on top, and average scanned densities of each protein shown in arbitrary units (AU) are shown on the bottom. B, Representative autoradiogram of plasma showing newly synthesized apoB at the 120-min time point. Ldlr / mice were treated for 1 wk with vehicle or T3 by gavage, injected with [35S]methionine, and Triton WR1339 and plasma (1 l) containing liver-secreted apoB was subjected to SDS-PAGE analysis. Average scanned densities (AU) of each protein are shown on bottom. C, Triglyceride production in Triton WR1339-treated Ldlr / mice receiving control vehicle or T3 by gavage for 1 wk. P values: *, P 0.05; and **, P 0.01. Con, Control. D, WT C57BL/6 mice were placed on a Western diet for 1 wk and then maintained on the diet and treated with T3, 0.75 mg/kg, by daily gavage for 1 wk. LDLR were detected by Western blot analysis. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. IDL/LDL cholesterol. In Ldlr / mice HDL cholesterol levels were reduced only by T3. In C57BL/6 both high-dose T2 and T3 reduced HDL cholesterol. Triglyceride levels were relatively unaffected by T3 and T2 despite the marked reduction in VLDL/LDL cholesterol. This suggested that the residual lipoproteins were relatively enriched with triglyceride and depleted of cholesterol. Assessment of plasma levels of apoB48 and apoB100 One possible action of thyroid hormones is to increase apoB RNA editing, which should decrease apoB100 and increase apoB48 ( 16, 17 ). Figure 1A shows that T3 and T2 reduced both apoB100 and apoB48 in Ldlr / mice to a similar extent. These data suggest that apoB RNA editing is not likely to be involved in T3- and T2-induced cholesterol reduction. * B100 Con WT C57BL/6 Con T3 Liver lipoprotein production We next assessed whether T3 alters lipoprotein production. Both apoB100 and apoB48 secretion into plasma were markedly reduced by T3 (Fig. 1B). Surprisingly, triglyceride secretion was almost doubled by T3 treatment (Fig. 1C). Thus, the liver produces fewer, but more triglyceride-rich, lipoproteins. T3-mediated changes in liver gene and protein expression B48 We first assessed whether in WT mice, T3 regulated LDLR. It did not; liver expression of LDLR is shown in Fig. 1D. T3 T3 increased mRNA levels for the gene (Me1) coding for malic enzyme 1 (Fig. 2A), a gene known to be induced by activation of hepatic TR ( 7 ). Although T2 also tended to increase this mRNA the changes were not statically significant. Me2 was not significantly altered by either T3 or T2 treatment (Fig. 2B). Thyroid treatment did not alter mRNA levels of LDLR-related protein 1 (Lrp1), proteoglycan syndecan 1 (Sdc1), or its sulfation enzyme N-deacetylase/N-sulfotransferase 1 (Ndst1), Apob, or microsomal triglyceride transfer protein (Mttp) (Fig. 2, C?E, G, and H). Scavenger receptor B-1 (Srb1) mRNA levels were reduced by thyroid, although HDL levels were not increased (Fig. 2F). Western blot analysis also showed that hepatic LRP1 and SR-B1 proteins were not increased by T3 or T2 (Fig. 2I). Taken together, the reduction in lipoprotein production (Fig. 1) with no changes in liver lipoprotein receptors (Fig. 2I) is likely to explain the reduced levels of circulating cholesterol in thyroid hormone-treated Ldlr / mice. Discussion Despite the long history of research into the relationship of thyroid hormones and lipid metabolism, the precise molecular pathways by which thyroid hormones affect cholesterol are, surprisingly, more complicated than the literature suggests. Although it has been reported that thyroid hormones modulate the LDLR and apoB editing, our studies show that these processes are not responsible M e2 T3 Sdc1 CON Con T2 Con Con T3 T2 Con C A D G H 8 e 6 g n a h4 C d l o F2 B E I 4 e3 g n a h2 C d l o F1 0 4 e3 g n a h2 C d l o F1 0 Con T3 T2 LRP1 for thyroid hormone reductions in circulating cholesterol, at least with the very high doses used in mice on a Western diet. Rather, we found that both T2 and T3 reduce circulating cholesterol exclusive of the LDLR and, unlike the reported effects of thyromimetics, also without increases in SR-B1. Even in WT mice, we were unable to show an increase in LDLR with T3 treatment. Finally, our kinetic data show that T3 increased liver production of triglycerides while at the same time it dramatically reduced apoB secretion. Our studies were not meant to investigate the use of thyroid hormone as a therapeutic agent ( 10 ), but to define a non-LDLR pathway that could be an important target for cholesterol reduction therapies. For this reason, we chose a T3 dose that was likely to reduce cholesterol levels. The low-dose T2 (1.25 mg/kg) given orally, 5-fold greater than ip T2 dose used by prior investigators ( 18 ), had only a small effect on plasma cholesterol levels. Therefore, we employed a 1 order of magnitude higher dose of T2, similar to the d-T2 dose used in humans ( 4 ), to obtain a cholesterol-lowering effect similar to that of T3. It should be noted that a similar dose of d-T2 reduced cholesterol, but was associated with cardiac toxicity in humans. We suspect that the dose that we used in mice would have had a similar toxicity because the T2-treated mice had heart enlargement and reductions in circulating levels of T4, indicative of pituitary suppression of the thyroid. Our studies are the first to probe the effects of thyroid hormones in WTD-fed mice lacking the LDLR. These studies reveal that the cholesterol-lowering effect of T2 and T3 in vivo does not require the LDLR. Two recent studies on the effects of thyromimetics on lipid metabolism showed an induction of SR-B1 with no changes in LDLR ( 11, 12 ). Van Berkel and associates ( 19, 20 ) have published two papers in which they hypothesized that SR-B1 is a remnant receptor, and induction of this receptor, as reported by others using thyromimetics, could have been a reason for the efficacy of T3 and T2 in our mice. However, we found no increase in SR-B1. Rat LDLR promoter contains thyroid-responsive element responsive to thyroid treatment ( 21 ). Evidence for a role of the LDLR in the cholesterol-reducing actions of thyroid hormones come from a recent report that thyromimetic, T-0681, reduced cholesterol in Apoe / but not in chow-fed Ldlr / mice ( 12 ). These data strikingly contrast with those we have obtained using Ldlr / mice and suggest that either T-0681 differs in action from T2 and T3 or that the dietary conditions altered responses to these hormones. As a first step toward uncovering a novel pathway that could increase plasma clearance of apoB-containing lipoproteins via thyroid hormone treatment, we assessed liver lipoprotein production. The dramatic reductions in liver production of apoB clearly implicate reduced production as a primary mechanism for cholesterol reduction. The results of our experiments can be compared with those of Davidson et al. ( 16 ) in chow-fed rats. Like these investigators, we observed decreased apoB100 secretion. In contrast, we found reduced apoB48 and also increased triglyceride secretion rates, whereas they reported no change in apoB48 or triglyceride secretion. The reduction in both forms of apoB means that production and not primarily editing was involved. Experimental thyroid deficiency is reported to not change lipoprotein production ( 22 ). Therefore, excess thyroid and hypothyroidism may affect lipoproteins via different mechanisms. Another difference between our studies and several in the literature is our use of a more physiologically relevant WTD because dietary absorption of cholesterol and triglyceride drives hepatic apoB production, especially in Ldlr / mice. What could reduce apoB production and at the same time increase triglyceride production? Our findings reported here are consistent with observations that thyroid increases triglycerides in some human subjects ( 23 ). This is thought to result from a peripheral action of thyroid hormone to enhance lipolysis, which in turn leads to increased free fatty acid release from adipose tissue. Under some conditions triglyceride removal may be balanced due to increases in lipoprotein lipase and hepatic lipase ( 24 ), and this results in a lack of changes in circulating triglyceride levels. Another process that might account for increased hepatic triglyceride production is reduced activation of the transcription factor farnesoid X receptor ( 25 ). In addition, studies have also shown that thyroid positively regulates the expression of the genes encoding CYP7A1 ( 26 ), the rate-limiting enzyme for the biosynthesis of bile acids. Hepatic overexpression of CYP7A1 significantly reduces plasma LDL cholesterol in Ldlr / mice ( 27 ). The possible role of bile acid homeostasis in the thyroid effect on plasma cholesterol levels is currently under investigation. Our findings have potential clinical significance. Newer methods to reduce plasma cholesterol may be of clinical relevance in several situations: 1) Non-LDLR-mediated therapies could be used for treatment of homozygous familial hypercholesterolemia. Because statins induce sterol-regulatory element binding protein 2 and LDLR expression, leading to more rapid clearance of LDL from the bloodstream, they are relatively ineffective in patients with homozygous hypercholesterolemia ( 28 ). The current treatment for these patients is often liver transplantation ( 29 ). Thus, there is a need for other cholesterollowering therapies that do not require a functional LDLR. 2) Statin medications for cholesterol have significant side effects that occur in up to 10% of patients ( 30 ). 3) Statins are not sufficient for all patients. Our studies illustrate a method for LDL cholesterol reduction via reducing apoB production and offer the hope of finding therapies that work via a similar mechanism but without peripheral organ toxicity. 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Goldberg, Ira J., Huang, Li-Shin, Huggins, Lesley A., Yu, Shuiqing, Nagareddy, Prabhakara R., Scanlan, Thomas S., Ehrenkranz, Joel R.. Thyroid Hormone Reduces Cholesterol via a Non-LDL Receptor-Mediated Pathway, Endocrinology, 2012, 5143-5149, DOI: 10.1210/en.2012-1572