gc-1-compound and Non-alcoholic-Fatty-Liver-Disease

gc-1-compound has been researched along with Non-alcoholic-Fatty-Liver-Disease* in 5 studies

Reviews

2 review(s) available for gc-1-compound and Non-alcoholic-Fatty-Liver-Disease

ArticleYear
Thyroid Hormone Analogues: An Update.
    Thyroid : official journal of the American Thyroid Association, 2020, Volume: 30, Issue:8

    The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

    Topics: Acetates; Anilides; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Diiodothyronines; Drug Design; Dyslipidemias; Humans; Liver Diseases; Male; Mice; Mutation; Non-alcoholic Fatty Liver Disease; Phenols; Pyridazines; Rats; Signal Transduction; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones; Thyronines; Triiodothyronine; Uracil

2020
GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease.
    Gene expression, 2017, 11-27, Volume: 17, Issue:4

    Thyroid hormones (THs), namely, 3,5,3'-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodo-l-thyronine (thyroxine or T4), influence a variety of physiological processes that have important implications in fetal development, metabolism, cell growth, and proliferation. While THs elicit several beneficial effects on lipid metabolism and improve myocardial contractility, these therapeutically desirable effects are associated to a thyrotoxic state that severely limits the possible use of THs as therapeutic agents. Therefore, several efforts have been made to develop T3 analogs that could retain the beneficial actions (triglyceride, cholesterol, obesity, and body mass lowering) without the adverse TH-dependent side effects. This goal was achieved by the synthesis of TRβ-selective agonists. In this review, we summarize the current knowledge on the effects of one of the best characterized TH analogs, the TRβ1-selective thyromimetic, GC-1. In particular, we review some of the effects of GC-1 on different liver disorders, with reference to its possible clinical application. A brief comment on the possible therapeutic use of GC-1 in extrahepatic disorders is also included.

    Topics: Acetates; Animals; Carcinoma, Hepatocellular; Cell Proliferation; Hepatocytes; Humans; Liver Diseases; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Phenols; Thyroid Hormone Receptors beta

2017

Other Studies

3 other study(ies) available for gc-1-compound and Non-alcoholic-Fatty-Liver-Disease

ArticleYear
Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH).
    PloS one, 2020, Volume: 15, Issue:12

    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.

    Topics: Acetates; Angiopoietin-Like Protein 4; Animals; Cell Line, Tumor; Cholesterol, LDL; Diet, High-Fat; Disease Models, Animal; Drug Evaluation, Preclinical; Hepatocytes; Humans; Iodide Peroxidase; Liver; Malate Dehydrogenase; Male; Non-alcoholic Fatty Liver Disease; Organophosphonates; Phenols; Primary Cell Culture; Pyridazines; Rats; Thyroid Hormone Receptors beta; Transcription, Genetic; Uracil

2020
The amelioration of hepatic steatosis by thyroid hormone receptor agonists is insufficient to restore insulin sensitivity in ob/ob mice.
    PloS one, 2015, Volume: 10, Issue:4

    Thyroid hormone receptor (TR) agonists have been proposed as therapeutic agents to treat non-alcoholic fatty liver disease (NAFLD) and insulin resistance. We investigated the ability of the TR agonists GC-1 and KB2115 to reduce hepatic steatosis in ob/ob mice. Both compounds markedly reduced hepatic triglyceride levels and ameliorated hepatic steatosis. However, the amelioration of fatty liver was not sufficient to improve insulin sensitivity in these mice and reductions in hepatic triglycerides did not correlate with improvements in insulin sensitivity or glycemic control. Instead, the effects of TR activation on glycemia varied widely and were found to depend upon the time of treatment as well as the compound and dosage used. Lower doses of GC-1 were found to further impair glycemic control, while a higher dose of the same compound resulted in substantially improved glucose tolerance and insulin sensitivity, despite all doses being equally effective at reducing hepatic triglyceride levels. Improvements in glycemic control and insulin sensitivity were observed only in treatments that also increased body temperature, suggesting that the induction of thermogenesis may play a role in mediating these beneficial effects. These data illustrate that the relationship between TR activation and insulin sensitivity is complex and suggests that although TR agonists may have value in treating NAFLD, their effect on insulin sensitivity must also be considered.

    Topics: Acetates; Anilides; Animals; Blood Glucose; Body Temperature; Dose-Response Relationship, Drug; Enzyme Induction; Glucose-6-Phosphatase; Insulin Resistance; Male; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Phenols; Receptors, Thyroid Hormone; Time Factors

2015
Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways.
    American journal of physiology. Endocrinology and metabolism, 2013, Jul-01, Volume: 305, Issue:1

    Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.

    Topics: Acetates; Anilides; Animals; Dietary Fats; Fatty Liver; Gene Expression; Gluconeogenesis; Glucose Transporter Type 4; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Male; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Phenols; Rats; Rats, Sprague-Dawley; Signal Transduction; Thyroid Hormone Receptors beta; Triglycerides

2013