Thyroid mimetic as an option for lowering low-density lipoprotein

Grundy, Scott M.

doi:10.1073/pnas.0705959104

Cited by 4 publications

(1 citation statement)

References 21 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These actions of thyroid hormone have made isoform-selective TR agonists highly attractive targets for drug development, and trials with these agents show great promise [6]. The usual experience with nuclear receptor agonists, however, is unanticipated actions of these ligands on other pathways [73]. It is important that the mechanisms of interactions of TR with these other metabolic regulators be investigated to identify the range of potential interactions and optimize the therapeutic effects of agents that target these pathways.…”

Section: Future Questionsmentioning

confidence: 99%

Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation

Liu

Brent

2010

Trends in Endocrinology & Metabolism

187

131

View full text Add to dashboard Cite

Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis, and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor (TR) interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors (PPARs), liver X receptor (LXR), and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor (RXR) heterodimer partners, DNA binding sites, and transcriptional co-factors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways, and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity, and diabetes. Thyroid Hormone and MetabolismThyroid hormone is a key metabolic regulator coordinating short-term and long-term energy needs [1]. Significant metabolic changes are seen with variations in thyroid status in humans [2]. Hyperthyroidism, characterized by elevated serum thyroid hormone levels, is associated with accelerated metabolism, increased lipolysis, weight loss, increased hepatic cholesterol biosynthesis and excretion, and reduced serum cholesterol levels. Hypothyroidism, characterized by low serum thyroid hormone levels, is associated with reduced metabolism, reduced lipolysis, weight gain, reduced cholesterol clearance, and elevated serum cholesterol. With low food intake, nutrient and other feedback is integrated centrally to reduce thyroid hormone production, resulting in lower metabolic rate and shifting the body to an energy conservation mode [3]. In fact, body weight in humans is inversely correlated with thyroid hormone levels [4]. Many of the actions of thyroid hormone in metabolic regulation involve modulation of other metabolic signaling pathways (Table 1). Thyroid Hormone ActionThyroid hormone acts predominantly through its nuclear receptors, thyroid hormone receptor (TR) α and β, which are differentially expressed developmentally and in adult tissues [1]. TR isoform-specific metabolic functions have been identified, and selective TR agonists have been developed to stimulate specific metabolic pathways [5,6]. The functional TR complex consists Address Correspondences: Gregory A. Brent, Molecular Endocrinology Laboratory, Building 114, Room 230, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA 90073, Phone 301 268-3735, FAX 310 268-4982, gbrent@ucla.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could a...

show abstract

Section: Future Questionsmentioning

confidence: 99%

Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation

Liu

Brent

2010

Trends in Endocrinology & Metabolism

187

131

View full text Add to dashboard Cite

show abstract

Is the Future of Statins Aligned with New Novel Lipid Modulation Therapies?

Phan

Tóth

2013

Curr Atheroscler Rep

View full text Add to dashboard Cite

Dyslipidemia is an established risk factor for the development of atherosclerotic cardiovascular disease. Statin therapy has been proven in a number of clinical trials to lower the risk of acute cardiovascular events and is the mainstay of cholesterol treatment. Despite current optimal treatment for dyslipidemia, many patients fail to reach adequate cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. Given this residual risk, there is a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins and, in some cases, raise levels of high-density lipoproteins. A number of novel lipid-altering therapies have been developed and are currently in clinical trials. In this review, we discuss these promising therapies, which include PCSK9 inhibitors, apolipoprotein B antisense oligonucleotides, microsomal transfer protein inhibitors, thyroid mimetics, and cholesteryl ester transfer protein inhibitors. Although statin therapy is the current recommended primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic heart disease.

show abstract

Thyroid Hormone Regulation of Metabolism

Mullur

Liu

Brent

2014

Physiological Reviews

1,731

1,299

View full text Add to dashboard Cite

Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

show abstract

Thyroid mimetic as an option for lowering low-density lipoprotein

Cited by 4 publications

References 21 publications

Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation

Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation

Is the Future of Statins Aligned with New Novel Lipid Modulation Therapies?

Thyroid Hormone Regulation of Metabolism

Contact Info

Product

Resources

About