Thyroid hormone analogues and derivatives: Actions in fatty liver (original) (raw)
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Thyroid, 2019
Background-Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary-THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-L-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions-TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/
Hepatology, 2008
Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, with a prevalence ranging from 10% to 30%. The use of thyroid hormone receptor (TR) agonists for the treatment of NAFLD has not been considered viable because thyroid hormones increase free fatty acid (FFA) flux from the periphery to the liver, induce hepatic lipogenesis, and therefore could potentially cause steatosis. MB07811 is an orally active HepDirect prodrug of MB07344, a liver-targeted TR- agonist. The purpose of these studies was to assess the effects of MB07811 on whole body and liver lipid metabolism of normal rodents and rodent models of hepatic steatosis. In the current studies, MB07811 markedly reduced hepatic steatosis as well as reduced plasma FFA and triglycerides. In contrast to MB07811, T 3 induced adipocyte lipolysis in vitro and in vivo and had a diminished ability to decrease hepatic steatosis. This suggests the influx of FFA from the periphery to the liver may partially counteract the antisteatotic activity of T 3. Clearance of liver lipids by MB07811 results from accelerated hepatic fatty acid oxidation, a known consequence of hepatic TR activation, as reflected by increased hepatic mitochondrial respiration rates, changes in hepatic gene expression, and increased plasma acyl-carnitine levels. Transaminase levels remained unchanged, or were reduced, and no evidence for liver fibrosis or other histological liver damage was observed after treatment with MB07811 for up to 10 weeks. Additionally, MB07811, unlike T 3 , did not increase heart weight or decrease pituitary thyroid-stimulating hormone beta (TSH) expression. Conclusion: MB07811 represents a novel class of liver-targeted TR agonists with beneficial low-density lipoprotein cholesterollowering properties that may provide additional therapeutic benefit to hyperlipidemic patients with concomitant NAFLD. (HEPATOLOGY 2009;49:407-417.) See Editorial on Page 348 N onalcoholic fatty liver disease (NALFD) is one of the most common forms of chronic liver disease, with a prevalence ranging from 10% to 30%. 1,2 Under certain conditions, NAFLD can progress to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. 3,4 NAFLD occurs frequently in obese, type 2 diabetic patients 5 and may contribute to the pathological condition underlying hepatic insulin resistance in these patients. 6 Moreover, patients with impaired glucose tolerance and NALFD have an elevated risk of cardiovascular mortality. 3 Although the specific mechanism(s) leading from simple steatosis to steatosis associated with an adverse clinical outcome are under investigation, identification of a potential therapy for NAFLD could have considerable medical utility. 4 Thyroid hormones (such as 3,3Ј,5-triiodo-L-thyronine; T 3
Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry, 2015
Background: Non-alcoholic fatty liver disease is one of the most common chronic liver diseases. Given the lack of definitive documentation for the effect of thyroid gland disorders on fatty liver, this study was conducted to determine the relationship between serum thyroid hormones levels and fatty liver in patients referring to Imam Hossain Hospital in Shahroud, in 2016. Methods: This case-control study was performed on 150 patients. The case group consisted of fatty liver patients whose disease was diagnosed based on laboratory and ultrasound findings, and a control group of patients with any other diseases without fatty liver. After liver ultrasonography, blood samples were taken from all patients and thyroid hormones levels were measured. Results: Of the 150 patients examined, the mean BMI of the patients was 24.79±6.9 kg / m2, which was significantly higher in the case group (P<0.012). The mean FBS level, was 131.5±83.5 mg / dl, which was significantly higher (P<0.001) in the case group. Similarly, the mean of TG was 245.5±128.5 mg / dl, which was significantly higher in the case group (P<0.047). On the other hand, the mean LDL of patients was 145.5±30.5 mg / dl, which was significantly higher (P<0.012) in patients with fatty liver. Further, the mean TSH of patients was significantly higher in the case group (P<0.014). Finally, there were no significant differences between the two groups regarding other variables. Conclusions: The results of this study suggested that thyroid gland disorders, especially hypothyroidism, were significantly higher in patients with fatty liver than in other patients. Nevertheless, they could not be influential in the incidence, exacerbation and persistence of fatty liver as a favorable factor.
International Journal of Molecular Sciences, 2017
The thyroid hormones (THs) 3,3 ,5,5-tetraiodo-L-thyronine (T4) and 3,5,3-triiodo-L-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-L-thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer.
Metabolites
We performed a systematic review of the mechanisms of thyroid hormones (THs) associated with metabolic dysfunction associated with fatty liver disease (MAFLD). This systematic review was registered under PROSPERO (CRD42022323766). We searched the MEDLINE (via PubMed) and Embase databases from their inception to March 2022. We included studies that assessed thyroid function by measuring the serum level of THs and those involved in MAFLD. We excluded reviews, case reports, editorials, letters, duplicate studies and designed controls. Forty-three studies included MAFLD, eleven analyzed THs, and thirty-two evaluated the mechanisms of THs in MAFLD. Thyroid hormones are essential for healthy growth, development and tissue maintenance. In the liver, THs directly influence the regulation of lipid and carbohydrate metabolism, restoring the homeostatic state of the body. The selected studies showed an association of reduced levels of THs with the development and progression of MAFLD. In paral...
Proceedings of the National Academy of Sciences, 2007
Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRβ isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRβ-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2 R ,4 S )-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the ...
TG68, a Novel Thyroid Hormone Receptor-β Agonist for the Treatment of NAFLD
International Journal of Molecular Sciences
Activation of thyroid hormone receptor β (THRβ) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a novel THRβ agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THRβ agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THRβ, as confirmed by increased mRNA levels of Deiodinase-1 and Malic enzyme-1, and changes in lipid metabolism, as revealed by increased expression of Acyl-CoA Oxidase-1 a...
Endocrinology, 2012
Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the United States and is strongly associated with hepatic insulin resistance. We examined whether the thyroid hormone receptor-␣ (Thra) would be a potential therapeutic target to prevent diet-induced NAFLD and insulin resistance. For that purpose, we assessed insulin action in high-fat diet-fed Thra gene knockout (Thra-0/0) and wild-type mice using hyperinsulinemic-euglycemic clamps combined with 3 H/ 14 C-labeled glucose to assess basal and insulin-stimulated rates of glucose and fat metabolism. Body composition was assessed by 1 H magnetic resonance spectroscopy and energy expenditure by indirect calorimetry. Relative rates of hepatic glucose and fat oxidation were assessed in vivo using a novel proton-observed carbon-edited nuclear magnetic resonance technique. Thra-0/0 were lighter, leaner, and manifested greater whole-body insulin sensitivity than wild-type mice during the clamp, which could be attributed to increased insulin sensitivity both in liver and peripheral tissues. Increased hepatic insulin sensitivity could be attributed to decreased hepatic diacylglycerol content, resulting in decreased activation of protein kinase C and increased insulin signaling. In conclusion, loss of Thra protects mice from high-fat diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. Therefore, thyroid receptor-␣ inhibition represents a novel pharmacologic target for the treatment of NAFLD, obesity, and type 2 diabetes. (Endocrinology 153: 583-591, 2012) N onalcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in the United States, affecting one in four adults, and is a major risk factor for the development of type 2 diabetes (1). Current pharmacologic treatment of NAFLD is disappointing, relying mostly on weight loss (2-4), although insulin-sensitizing agents, such as thiazolidinediones, have been shown to decrease hepatic steatosis by promoting fat redistribution to the sc adipose tissue (5, 6). Thyroid hormone plays a role in diverse important metabolic pathways in lipid and glucose metabolisms and regulation of body weight (7). Thyroid hormone acts predominantly through its nuclear receptors, thyroid hormone receptors ␣ and , which differ in their tissue distribution (8). Although thyroid hormone therapy for the treatment of obesity and NAFLD would be deleterious in euthyroid patients due to associated cardiovascular side effects, such as tachycardia and hyperten