scholarly journals Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 6136-6144 ◽  
Author(s):  
Jean Z. Lin ◽  
Alexandro J. Martagón ◽  
Willa A. Hsueh ◽  
John D. Baxter ◽  
Jan-Åke Gustafsson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Cholesterol ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Reduce Serum Cholesterol

Abstract The majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T3 and the thyroid hormone receptor-β selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol-lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective.

scholarly journals Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0240338
Author(s):  
Xuan G. Luong ◽  
Sarah K. Stevens ◽  
Andreas Jekle ◽  
Tse-I Lin ◽  
Kusum Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Fatty Acid Biosynthesis ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Liver Fat ◽  
Alcoholic Steatohepatitis

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.

scholarly journals Dronerarone Acts as a Selective Inhibitor of 3,5,3′-Triiodothyronine Binding to Thyroid Hormone Receptor-α1: In Vitro and in Vivo Evidence

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 552-558 ◽  
Author(s):  
H. C. van Beeren ◽  
W. M. C. Jong ◽  
E. Kaptein ◽  
T. J. Visser ◽  
O. Bakker ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Receptor Protein ◽  
Qtc Interval

Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro , Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo , AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRα1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRα1-selective inhibitor.

scholarly journals Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3699-3712 ◽  
Author(s):  
J. H. Duncan Bassett ◽  
Alan Boyde ◽  
Tomas Zikmund ◽  
Holly Evans ◽  
Peter I. Croucher ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Skeletal Dysplasia ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Genetic Disorder ◽  
Dominant Negative ◽  
Skeletal Maturation ◽  
Prolonged Treatment ◽  
Causative Mutation ◽  
Dominant Negative Mutant

Abstract A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1PV/+ mice express a similar potent dominant-negative mutant TRα1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.

scholarly journals KIF13B enhances the endocytosis of LRP1 by recruiting LRP1 to caveolae

2014 ◽  
Vol 204 (3) ◽  
pp. 395-408 ◽  
Author(s):  
Yoshimitsu Kanai ◽  
Daliang Wang ◽  
Nobutaka Hirokawa
Keyword(s):  
Plasma Membrane ◽  
Factor Viii ◽  
Serum Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Motor Protein ◽  
Low Density ◽  
Related Protein ◽  
Caveolin 1

Multifunctional low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) recognizes and internalizes a large number of diverse ligands, including LDL and factor VIII. However, little is known about the regulation of LRP1 endocytosis. Here, we show that a microtubule-based motor protein, KIF13B, in an unexpected and unconventional function, enhances caveolin-dependent endocytosis of LRP1. KIF13B was highly expressed in the liver and was localized on the sinusoidal plasma membrane of hepatocytes. KIF13B knockout (KO) mice showed elevated levels of serum cholesterol and factor VIII, and KO MEFs showed decreased uptake of LDL. Exogenous KIF13B, initially localized on the plasma membrane with caveolae, was translocated to the vesicles in the cytoplasm with LRP1 and caveolin-1. KIF13B bound to hDLG1 and utrophin, which, in turn, bound to LRP1 and caveolae, respectively. These linkages were required for the KIF13B-enhanced endocytosis of LRP1. Thus, we propose that KIF13B, working as a scaffold, recruits LRP1 to caveolae via LRP1–hDLG1–KIF13B–utrophin–caveolae linkage and enhances the endocytosis of LRP1.

scholarly journals PATIENTS WITH COMBINED HYPERLIPIDEMIA

2020 ◽  
pp. 1-2
Author(s):  
Nirmal Garbadu
Keyword(s):  
Genetic Disorder ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cell Surface Receptor ◽  
Monogenic Disease ◽  
Atherosclerotic Cardiovascular Disease ◽  
Apo B ◽  
Ldl Catabolism

Combined Hyperlipidaemia or Familial hypercholesterolemia (FH) is a frequent genetic disorder viz., an autosomal codominant disorder, characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease1. The expression of the genetic potential for these lipid disorders is a complex process which only occurs when genetically inherited predisposing factors interact with other metabolic factors that exacerbate hyperlipidaemia2. Adipose tissue secretes several adipocytokines (i.e. adiponectin, leptin, and others) that regulate appetite, immunity, inflammation, and glucose/lipid metabolism3. Basically, hepatocytes and steroid hormone-producing cells have LDL receptors. Normally, these cell surface receptor for LDL removes cholesterol-carrying LDL from the plasma by a process of receptor-mediated endocytosis. However, mutations in the LDL receptor gene results in FH4. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (apo B), and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals, no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease (CVD; ASCVD) risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease 1.

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

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5143-5149 ◽  
Author(s):  
Ira J. Goldberg ◽  
Li-Shin Huang ◽  
Lesley A. Huggins ◽  
Shuiqing Yu ◽  
Prabhakara R. Nagareddy ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Knockout Mice ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Cholesterol Reduction

Abstract 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.

New Horizons in the Pathogenesis, Pathophysiology and Treatment of Familial Hypercholesterolaemia

2019 ◽  
Vol 24 (31) ◽  
pp. 3599-3604 ◽  
Author(s):  
Margus Viigimaa ◽  
Silver Heinsar ◽  
Dragan Lovic ◽  
Alexandra Katsimardou ◽  
Alexia Piperidou ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Familial Hypercholesterolaemia ◽  
Genetic Disorder ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Public Health Problem ◽  
Atherosclerotic Cardiovascular Disease ◽  
Significant Public Health Problem ◽  
Significant Public Health

Background: Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis. Objective: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH. Results: The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its pathogenesis. An Autosomal Recessive Hypercholesterolaemia (ARH) is another cause, very rare (1/2.500 births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis. Conclusion: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9, while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its accumulation and subsequent CVD earlier than in the general population.

Activity of low-density lipoprotein receptors as estimated from concentrations of apolipoprotein B and C-II in serum.

1988 ◽  
Vol 34 (11) ◽  
pp. 2224-2227 ◽  
Author(s):  
H Ito ◽  
C Naito ◽  
H Hayashi ◽  
M Kawamura
Keyword(s):  
Serum Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Activity ◽  
Total Serum ◽  
Total Serum Cholesterol ◽  
Low Density ◽  
Apo B ◽  
Apo E

Abstract The correlation between low-density lipoprotein (LDL) receptor activity and concentrations of lipids and apolipoproteins in serum was examined in 12 subjects with heterozygous familial hypercholesterolemia (FH) and in four with non-FH type II hyperlipoproteinemia. Concentrations of high-density lipoprotein cholesterol and of apolipoproteins (apo) A-I, C-II, and C-III were significantly positively correlated with LDL receptor activity, whereas LDL receptor activity was significantly inversely correlated with LDL cholesterol and apo B concentrations, and with apo ratios B/A-I and B/A-II. Neither total serum cholesterol, triglyceride, phospholipid, apo A-I, nor apo E concentrations correlated significantly with LDL receptor activity. Multiple regression analysis, with LDL receptor activity as the dependent variable, revealed concentrations of apo B and apo C-II to be the principal determinant factors. To confirm this, we subsequently calculated the LDL receptor activities before and after administration of CS-514, an inhibitor of hydroxymethylglutaryl-CoA reductase (EC 1.1.1.88), which increases the hepatic LDL receptor activity and decreases the concentration of cholesterol in serum. This drug increased calculated LDL receptor activities significantly, with a significant decrease in serum cholesterol.

scholarly journals Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

2020 ◽  
Author(s):  
Xuan G. Luong ◽  
Sarah K. Stevens ◽  
Andreas Jekle ◽  
Tse-I Lin ◽  
Kusum Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Fatty Acid Biosynthesis ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Liver Fat ◽  
Alcoholic Steatohepatitis

AbstractThyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.

Sign in / Sign up

Export Citation Format

Share Document