Lipid lowering with thyroid hormone and thyromimetics

Angelin, Bo; Rudling, Mats

doi:10.1097/mol.0b013e3283402e9c

Cited by 66 publications

(58 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, it is obvious that while the increase in LDL-C with age in males was rather similar to that seen in females, there was no evidence of an increase in PCSK9 in men. Other hormone defi ciencies, such as those of growth hormone ( 15 ) and thyroid hormone ( 26 ), could contribute to the age-dependent reduction of LDLR function and ensuing increase in circulating LDL-C. In particular, the potential role of testosterone (in both genders) still remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Ghosh

Gälman

Rudling

et al. 2015

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Ghosh

Gälman

Rudling

et al. 2015

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

“…Moreover, they are powerful agents in counteracting hyperlipidemia and reducing body weight. However, unwanted effects on heart, bone, or muscle restrict their use as therapeutically active compounds for obesity-related diseases (Angelin & Rudling 2010).…”

Section: Introductionmentioning

confidence: 99%

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

Lietzow

Golchert

Homuth

et al. 2016

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T 2 ) acts as a metabolically active substance affecting whole-body energy metabolism and hepatic lipid handling in a desirable manner. Considering possible adverse effects regarding thyromimetic action of 3,5-T 2 treatment in rodents, the current literature remains largely controversial. To obtain further insights into molecular mechanisms and to identify novel target genes of 3,5-T 2 in liver, we performed a microarray-based liver tissue transcriptome analysis of male lean and diet-induced obese euthyroid mice treated for 4 weeks with a dose of 2.5 µg/g bw 3,5-T 2 . Our results revealed that 3,5-T 2 modulates the expression of genes encoding Phase I and Phase II enzymes as well as Phase III transporters, which play central roles in metabolism and detoxification of xenobiotics. Additionally, 3,5-T 2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T 2 in mouse liver. Interestingly, 3,5-T 2 in obese but not in lean mice influences the expression of genes relevant for cholesterol and steroid biosynthesis, suggesting a novel role of 3,5-T 2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T 2 in lean and diet-induced obese male mice alters the expression of genes encoding hepatic xenobiotic-metabolizing enzymes that play a substantial role in catabolism and inactivation of xenobiotics and TH and are also involved in hepatic steroid and lipid metabolism. The administration of this high dose of 3,5-T 2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T 2 as pharmacological hypolipidemic agent should be considered with caution.3,5-T 2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

show abstract

“…The involvement of THs in lipids metabolism was first reported in 1930, 1) and since then, accumulating evidence has shown that THs lower cholesterol levels in patients with hypercholesterolemia. [2][3][4] TH synthesis and secretion are strictly regulated by the hypothalamic/pituitary/thyroid (HPT) axis, and their physiological action is modulated via two homologous TH receptors, TRα and TRβ, which belong to the nuclear receptor superfamily of ligand-dependent transcription factors. 5) Because TH receptors are ubiquitously expressed in humans, plasma levels of circulating TH affect various physiological pathways and are associated with a number of pathological states such as hyperthyroidism, which is characterized by decreased serum cholesterol and triacylglycerides (TG) levels, body weight loss, tachycardia, palpitation, muscle wasting, and osteoporosis in postmenopausal women.…”

mentioning

confidence: 99%

<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

Takahashi

Asano²,

Maeda

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

We recently reported that the novel thyroid hormone receptor β (TRβ) selective agonists SKL-12846 and SKL-13784 reduce blood cholesterol levels without affecting thyroid-stimulating hormone (TSH) in cholesterol-fed rats. Our aim in this study was to elucidate what sets apart these SKL-compounds as TRβ agonists with no effect on TSH. To this end, we determined SKL-compounds pharmacokinetics and tissue distribution in normal rats and compared them to those of GC-1, a liver-selective TRβ agonist with concomitant effect on TSH. The present study explains why SKL-12846 and SKL-13784 have beneficial effects on lowering lipids without affecting heart rate and TSH production at the therapeutic dose in cholesterol-fed rats. In addition, we found that SKL-13784 shows no sign of escape phenomenon in fructose-fed rats. These results demonstrate the advantages of extremely high liver specificity to TRβ agonists. However, SKL-13784 has been found significantly to reduce endogenous T 4 levels at doses lower than its lipid-lowering dose, which may raise concerns over this compound's ability to alter thyroid hormone metabolism in the liver. While the mechanism by which SKL-13784 reduces endogenous T 4 levels is still unclear, our results would help design better liver-selective TRβ modulators.Key words thyroid hormone receptor β; thyroid stimulating hormone; lipid-lowering effect; GC-1 Thyroid hormones (THs) are known to influence all major metabolic pathways including growth, development, and lipids metabolism. The involvement of THs in lipids metabolism was first reported in 1930, 1) and since then, accumulating evidence has shown that THs lower cholesterol levels in patients with hypercholesterolemia.2-4) TH synthesis and secretion are strictly regulated by the hypothalamic/pituitary/thyroid (HPT) axis, and their physiological action is modulated via two homologous TH receptors, TRα and TRβ, which belong to the nuclear receptor superfamily of ligand-dependent transcription factors.5) Because TH receptors are ubiquitously expressed in humans, plasma levels of circulating TH affect various physiological pathways and are associated with a number of pathological states such as hyperthyroidism, which is characterized by decreased serum cholesterol and triacylglycerides (TG) levels, body weight loss, tachycardia, palpitation, muscle wasting, and osteoporosis in postmenopausal women. 6)Both academia and industry are making numerous efforts to separate TH beneficial effects such as cholesterol lowering and body weight loss from their other hormonal functions.3,7-10) Studies in TR-mutant mice suggest that TRβ is responsible for the cholesterol-lowering effect of TH.11-13) In addition, TRβ is predominantly expressed in the liver, where it accounts for approximately 80% of T 3 -binding TRs. 14)Therefore a number of liver-selective TRβ agonists have been developed. Among them, GC-1 (Fig. 1) and KB2115 showed promising clinical trial results, but never reached the market probably due to undesirable side effects.10) Considering their drawb...

show abstract

Lipid lowering with thyroid hormone and thyromimetics

Abstract: Liver-specific and β-selective thyroid hormone analogs activate a spectrum of favorable thyroid hormone actions that optimize lipid metabolism and promote cholesterol elimination. Further studies should establish long-term safety and potential clinical usefulness of thyromimetics.

Cited by 66 publications

References 45 publications

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

<i>In Vivo</i> Evaluation of 1-Benzyl-4-aminoindole-Based Thyroid Hormone Receptor β Agonists: Importance of Liver Selectivity in Drug Discovery

Contact Info

Product

Resources

About