Scholars@Duke
Paul Michael Yen

Paul Michael Yen

Professor of Medicine
Medicine, Endocrinology, Metabolism, and Nutrition
paul.yen@duke-nus.edu.sg
300 North Duke Street, Durham, NC 27701

Selected Publications

Actions of thyroid hormones and thyromimetics on the liver.

Journal Article Nat Rev Gastroenterol Hepatol · October 17, 2024 Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose ... Full text Link to item Cite

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

Journal Article Mol Metab · September 2024 OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label ... Full text Link to item Cite

Metabolic Messengers: Thyroid Hormones.

Journal Article Nat Metab · April 2024 Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear ... Full text Link to item Cite

Lower hepatic CBS and PEMT expression in advanced NAFLD: inferencing strategies to lower homocysteine with a mathematical model

Journal Article Metabolism and Target Organ Damage · January 1, 2024 Aim: Hepatic homocysteine (Hcy) accumulation promotes inflammation and fibrosis in experimental nonalcoholic fatty liver disease (NAFLD), while vitamin B12 and folate reduce hepatic Hcy and protect animals from nonalcoholic steatohepatitis. This suggests c ... Full text Cite

LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane.

Journal Article iScience · September 15, 2023 LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by repo ... Full text Link to item Cite

Lipidomics Workflow for Analyzing Lipid Profiles Using Multiple Reaction Monitoring (MRM) in Liver Homogenate of Mice with Non-alcoholic Steatohepatitis (NASH).

Journal Article Bio Protoc · July 5, 2023 Non-alcoholic steatohepatitis (NASH) is a condition characterized by inflammation and hepatic injury/fibrosis caused by the accumulation of ectopic fats in the liver. Recent advances in lipidomics have allowed the identification and characterization of lip ... Full text Link to item Cite

Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of citrin deficiency.

Journal Article Hum Mol Genet · May 18, 2023 Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis ... Full text Link to item Cite

Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.

Journal Article Biochim Biophys Acta Mol Basis Dis · April 2023 Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NA ... Full text Link to item Cite

Metabolomics to Assess Thyroid Hormone Status?

Journal Article The Journal of clinical endocrinology and metabolism · February 2023 Full text Cite

Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.

Journal Article J Hepatol · November 2022 BACKGROUND & AIMS: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it ... Full text Link to item Cite

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.

Journal Article Nat Commun · September 3, 2022 Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination ... Full text Link to item Cite

Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.

Journal Article Autophagy · September 2022 Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying ... Full text Link to item Cite

Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis.

Journal Article Thyroid · June 2022 Background: Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, lobular inflammation, and fibrosis. Thyroid hormone (TH) reduces steatosis; however, the therapeutic effect of TH on NASH-associated inflammation and fibrosis is not kno ... Full text Link to item Cite

MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism.

Journal Article Autophagy · December 2021 Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex s ... Full text Link to item Cite

Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression.

Journal Article Mol Metab · November 2021 OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAF ... Full text Link to item Cite

MTORC1 inhibition drives crinophagic degradation of glucagon.

Journal Article Mol Metab · November 2021 OBJECTIVE: Crinophagy is a secretory granule-specific autophagic process that regulates hormone content and secretion in endocrine cells. However, despite being one of the earliest described autophagic processes, its mechanism of action and regulation in m ... Full text Link to item Cite

MTORC1-dependent crinophagy regulates glucagon content in pancreatic α-cells.

Journal Article Autophagy · October 2021 Hormone synthesis and secretion is a highly regulated process governed by metabolic cues. Although peptide hormone action is largely governed by the rate of its synthesis and secretion by endocrine cells, and the levels of its receptors on the target cells ... Full text Link to item Cite

Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle.

Journal Article Endocrinology · August 1, 2021 Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone α (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined th ... Full text Link to item Cite

Increased Hepatic Fat Content in Patients with Resistance to Thyroid Hormone Beta.

Journal Article Thyroid · July 2021 Background: Thyroid hormone (TH) has important functions in controlling hepatic lipid metabolism. Individuals with resistance to thyroid hormone beta (RTHβ) who harbor mutations in the THRB gene experience loss-of-function of thyroid hormone receptor beta ... Full text Link to item Cite

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Journal Article Science translational medicine · June 2021 Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11 ... Full text Cite

Profiling retrospective thyroid function data in complete thyroidectomy patients to investigate the HPT axis set point (PREDICT-IT).

Journal Article J Endocrinol Invest · May 2021 BACKGROUND: The homeostatic euthyroid set point of the hypothalamus-pituitary-thyroid axis of any given individual is unique and oscillates narrowly within substantially broader normal population ranges of circulating free thyroxine (FT4) and thyroid-stimu ... Full text Link to item Cite

Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue.

Journal Article iScience · May 2021 Autophagy plays an important role in lipid breakdown, mitochondrial turnover, and mitochondrial function during brown adipose tissue (BAT) activation by thyroid hormone, but its role in BAT during adaptive thermogenesis remains controversial. Here, we exam ... Full text Cite

CD10 marks non-canonical PPARγ-independent adipocyte maturation and browning potential of adipose-derived stem cells.

Journal Article Stem Cell Res Ther · February 4, 2021 BACKGROUND: Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. However, limitations in our understanding ... Full text Link to item Cite

Hippo pathway effectors YAP and TAZ and their association with skeletal muscle ageing.

Journal Article J Physiol Biochem · February 2021 Skeletal muscle atrophy commonly occurs during ageing, thus pathways that regulate muscle mass may represent a potential therapeutic avenue for interventions. In this review, we explored the Hippo signalling pathway which plays an essential role in human o ... Full text Link to item Cite

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH.

Journal Article Nat Commun · January 4, 2021 IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in respo ... Full text Link to item Cite

Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease.

Journal Article Hepatoma Res · 2021 Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currentl ... Full text Link to item Cite

The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD.

Journal Article Hepatoma Res · 2021 Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. It comprises simple steatosis and non-alcoholic steatohepatitis (NASH), which can further progress to cirrhosis and hepatocellular carcinoma. The pathogenesis ... Full text Link to item Cite

Autophagic protein ULK1 regulates FOXM1 signalling in human hepatoma cells.

Journal Article Biochem Biophys Res Commun · November 19, 2020 Hepatocellular cancer (HCC) is one of the leading causes of mortality worldwide. Unfortunately, a limited choice of anti-cancer drugs is available for treatment, owing to their minimal efficacy and development of acquired resistance. Autophagy, a cellular ... Full text Link to item Cite

Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells.

Journal Article Front Cell Dev Biol · September 30, 2020 The hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating k ... Full text Link to item Cite

Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.

Journal Article STAR protocols · September 2020 Previously developed senescent primary fibroblast models have limited relevance to study age-related changes in metabolically active tissues such as the liver. Here, we describe a protocol to generate senescent cells from the mouse hepatic cell line, AML12 ... Full text Cite

Decreased autophagy and fuel switching occur in a senescent hepatic cell model system.

Journal Article Aging (Albany NY) · July 26, 2020 Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxid ... Full text Link to item Cite

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone.

Journal Article Int J Mol Sci · April 24, 2020 Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latt ... Full text Link to item Cite

Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk.

Journal Article Int J Mol Sci · March 31, 2020 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the ... Full text Link to item Cite

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases.

Journal Article Int J Mol Sci · February 28, 2020 The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including ... Full text Link to item Cite

Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia.

Journal Article Hum Mol Genet · January 15, 2020 Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase α catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, ther ... Full text Link to item Cite

Links between autophagy and disorders of glycogen metabolism - Perspectives on pathogenesis and possible treatments.

Journal Article Mol Genet Metab · January 2020 The glycogen storage diseases are a group of inherited metabolic disorders that are characterized by specific enzymatic defects involving the synthesis or degradation of glycogen. Each disorder presents with a set of symptoms that are due to the underlying ... Full text Link to item Cite

Diagnosis and treatment of hypothyroidism in the elderly.

Journal Article Endocrine · October 2019 The global population is aging with millions of people today living into their 90 s. Thyroid disease, particularly hypothyroidism, is widespread among all age groups, and it is expected to steadily increase as the population gets older. Clinical diagnosis ... Full text Link to item Cite

Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis.

Journal Article Gastroenterology · September 2019 BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibrobla ... Full text Link to item Cite

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists.

Journal Article Thyroid · September 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 ... Full text Link to item Cite

Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

Journal Article Autophagy · August 2019 Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cel ... Full text Link to item Cite

A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia.

Journal Article Thyroid · August 2019 Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and ... Full text Link to item Cite

Hyperthyroidism in the personalized medicine era: the rise of mathematical optimization.

Journal Article J R Soc Interface · June 28, 2019 Thyroid over-activity or hyperthyroidism constitutes a significant morbidity afflicting the world. The current medical practice of dose titration of anti-thyroid drug (ATD) treatment for hyperthyroidism is relatively archaic, being based on arbitrary and t ... Full text Link to item Cite

Titin truncations lead to impaired cardiomyocyte autophagy and mitochondrial function in vivo.

Journal Article Hum Mol Genet · June 15, 2019 Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy. TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTN ... Full text Link to item Cite

PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction.

Journal Article Hum Mol Genet · April 1, 2019 Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/frontotemporal dementia. In the current study, we generated isogenic human emb ... Full text Link to item Cite

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy.

Journal Article Autophagy · January 2019 The thyroid hormone triiodothyronine (T3) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T3 can induce thermogenesis by sympathetic innervation, little is known about its cel ... Full text Link to item Cite

Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia.

Journal Article Hum Mol Genet · January 1, 2019 Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke's Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and ... Full text Link to item Cite

Thyroid Hormone Status Regulates Skeletal Muscle Response to Chronic Motor Nerve Stimulation.

Journal Article Front Physiol · 2019 Although both exercise and thyroid hormone (TH) status can cause cellular and metabolic changes in skeletal muscle, the impact of TH status on exercise-associated changes is not well understood. Here, we examined the effects of TH status on muscle fiber ty ... Full text Link to item Cite

Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone.

Journal Article Int J Mol Sci · October 22, 2018 The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to ... Full text Link to item Cite

A fluorescent methylation-switchable probe for highly sensitive analysis of FTO N 6-methyladenosine demethylase activity in cells.

Journal Article Chem Sci · September 28, 2018 N 6-Methyladenosine (m6A) is one of the most abundant epigenetic modifications on mRNA. It is dynamically regulated by the m6A demethylases FTO and ALKBH5, which are currently attracting intense medical interest because of their strong association with sev ... Full text Link to item Cite

Low-Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients With Type 2 Diabetes Mellitus and NAFLD.

Journal Article J Clin Endocrinol Metab · July 1, 2018 CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and associated with significant morbidity and mortality. Thyroid hormone (TH) increases β-oxidation of fatty acids and decreases intrahep ... Full text Link to item Cite

Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function.

Journal Article Sci Signal · June 26, 2018 Thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA; also known as ERRα) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptome and ChIP-seq analyses and found that ... Full text Link to item Cite

Direct effects of thyroid hormones on hepatic lipid metabolism.

Journal Article Nat Rev Endocrinol · May 2018 It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has been associated with increased serum levels of triglycerides and cholesterol as well a ... Full text Link to item Cite

Pharmacological Inhibition of Lysosomal Activity as a Method For Monitoring Thyroid Hormone-induced Autophagic Flux in Mammalian Cells In Vitro.

Journal Article Methods Mol Biol · 2018 Autophagy is an evolutionarily conserved intracellular catabolic process that is essential for cellular housekeeping and nutrient homeostasis. Recently, we provided evidence that thyroid hormone (TH) is a major inducer of autophagy in mammalian cells. Here ... Full text Link to item Cite

Role of thyroid hormone in hepatic gene regulation, chromatin remodeling, and autophagy.

Journal Article Mol Cell Endocrinol · December 15, 2017 Thyroid hormone (TH) actions on development and metabolism have been studied ever since the discovery of thyroxine almost a century ago. Initial studies focused on the physiological and biochemical actions of TH. Later, the cloning of the thyroid hormone r ... Full text Link to item Cite

Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia.

Journal Article Mol Genet Metab · November 2017 GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabol ... Full text Link to item Cite

Increasing Dietary Medium-Chain Fatty Acid Ratio Mitigates High-fat Diet-Induced Non-Alcoholic Steatohepatitis by Regulating Autophagy.

Journal Article Sci Rep · October 25, 2017 Previous studies have demonstrated that saturated fatty acids (SFAs) are more lipotoxic than unsaturated fatty acids (UFAs) in inhibiting hepatic autophagy and promoting non-alcoholic steatohepatitis (NASH). However, there have been few studies have invest ... Full text Link to item Cite

Thyroid Hormone Signaling Pathways: Time for a More Precise Nomenclature.

Journal Article Endocrinology · July 1, 2017 Current literature makes a distinction between two pathways for thyroid hormone signaling: genomic and nongenomic. However, this classification is a source of confusion. We propose a clarification in the nomenclature that may help to avoid unproductive con ... Full text Link to item Cite

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer.

Journal Article Oncotarget · June 27, 2017 Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease d ... Full text Link to item Cite

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model.

Journal Article Thyroid · June 2017 BACKGROUND: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approxim ... Full text Link to item Cite

Metabolomic analysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet.

Journal Article Sci Rep · May 17, 2017 Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide, and is often associated with lipotoxic injury, defective mitochondrial function, and insulin resistance. Thyroid hormones (THs) are important regulators of hepatic lipid metaboli ... Full text Link to item Cite

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa).

Journal Article Sci Rep · March 20, 2017 Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, ... Full text Open Access Link to item Cite

Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging.

Journal Article Aging (Albany NY) · February 26, 2017 Aging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. ... Full text Link to item Cite

Reciprocal Crosstalk Between Autophagic and Endocrine Signaling in Metabolic Homeostasis.

Journal Article Endocr Rev · February 1, 2017 Autophagy is a cellular quality control and energy-providing process that is under strict control by intra- and extracellular stimuli. Recently, there has been an exponential increase in autophagy research and its implications for mammalian physiology. Aut ... Full text Link to item Cite

Loss of ULK1 increases RPS6KB1-NCOR1 repression of NR1H/LXR-mediated Scd1 transcription and augments lipotoxicity in hepatic cells.

Journal Article Autophagy · January 2, 2017 Lipotoxicity caused by saturated fatty acids (SFAs) induces tissue damage and inflammation in metabolic disorders. SCD1 (stearoyl-coenzyme A desaturase 1) converts SFAs to mono-unsaturated fatty acids (MUFAs) that are incorporated into triglycerides and st ... Full text Link to item Cite

Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation.

Journal Article Cell Death Dis · December 8, 2016 Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-ind ... Full text Link to item Cite

Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells.

Journal Article Biochem Biophys Res Commun · November 18, 2016 Short-chain fatty acids (SCFAs) are gut microbial fermentation products derived from dietary fiber sources. Although depletion of gut microflora has been linked to the development of liver disease, the direct effects of SCFAs on intracellular hepatic proce ... Full text Link to item Cite

Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

Journal Article Biochem Biophys Res Commun · October 21, 2016 Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NA ... Full text Link to item Cite

Physiological and Metabolic Changes During the Transition from Hyperthyroidism to Euthyroidism in Graves' Disease.

Journal Article Thyroid · October 2016 BACKGROUND: The serum metabolomic profile and its relationship to physiological changes during hyperthyroidism and restoration to euthyroidism are not known. This study aimed to examine the physiological, adipokine, and metabolomic changes that occur when ... Full text Link to item Cite

TSHβv-A New Bone to Pick.

Journal Article Endocrinology · September 2016 Full text Link to item Cite

Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice.

Journal Article Endocrinology · April 2016 Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult ... Full text Link to item Cite

Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency.

Journal Article J Hepatol · February 2016 BACKGROUND & AIMS: Glucose-6-phosphatase (G6Pase α, G6PC) deficiency, also known as von Gierke's disease or GSDIa, is the most common glycogen storage disorder. It is characterized by a decreased ability of the liver to convert glucose-6-phosphate (G6P) to ... Full text Link to item Cite

Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition.

Journal Article J Biol Chem · January 1, 2016 MTORC2-AKT is a key regulator of carbohydrate metabolism and insulin signaling due to its effects on FOXO1 phosphorylation. Interestingly, both FOXO1 and thyroid hormone (TH) have similar effects on carbohydrate and energy metabolism as well as overlapping ... Full text Link to item Cite

Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle.

Journal Article Endocrinology · January 2016 Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in ... Full text Link to item Cite

Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD.

Journal Article Cell Biosci · 2016 Non-alcoholic fatty liver disease (NAFLD) is a fast-growing silent epidemic that is present in both developed and developing countries. Initially thought as a benign deposition of lipids in the liver, it now has been shown to be a major risk factor for typ ... Full text Link to item Cite

Mechanisms for Thyroid Hormone Action in the CNS

Chapter · January 1, 2016 This chapter aims to summarize our recent understanding about the action of thyroid hormone (TH) in the CNS. The topics will include the molecular action of TH at genomic and non-genomic levels and its impact on the physiology of brain. ... Full text Cite

Classical nuclear hormone receptor activity as a mediator of complex biological responses: a look at health and disease.

Journal Article Best Pract Res Clin Endocrinol Metab · August 2015 Nuclear hormone receptors are a large family of receptors that bind a wide range of lipolic hormones and intracellular ligands. They act as ligand-inducible transcription factors to regulate the expression of target genes and play important roles in normal ... Full text Link to item Cite

An integrative approach identified genes associated with drug response in gastric cancer.

Journal Article Carcinogenesis · April 2015 Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differ ... Full text Link to item Cite

Unliganded TRs regulate growth and developmental timing during early embryogenesis: Evidence for a dual function mechanism of TR action

Journal Article Cell and Bioscience · March 2, 2015 © 2015 Yen; licensee BioMed Central. Recent genetic studies in the anuran Xenopus tropicalis reveal surprising new roles of thyroid hormone receptor in regulating growth and developmental timing in the absence of thyroid hormone. ... Full text Cite

Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling.

Journal Article Autophagy · 2015 Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T3) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism ... Full text Link to item Cite

Studies of molecular mechanisms associated with increased deiodinase 3 expression in a case of consumptive hypothyroidism.

Journal Article J Clin Endocrinol Metab · November 2014 CONTEXT: Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to increased catabolic activity of type 3 iodothyronine deiodinase (DIO3) that can occur in large tumors. PATIENTs with CH typically present with markedly increased requirements ... Full text Link to item Cite

Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism.

Journal Article Trends Endocrinol Metab · October 2014 Thyroid hormone (TH) has important roles in regulating hepatic lipid, cholesterol, and glucose metabolism. Recent findings suggest that clinical conditions such as non-alcoholic fatty liver disease and type 2 diabetes mellitus, which are associated with dy ... Full text Link to item Cite

Differential AMPK phosphorylation by glucagon and metformin regulates insulin signaling in human hepatic cells.

Journal Article Biochem Biophys Res Commun · May 16, 2014 Insulin and glucagon signaling in the liver are major contributors to glucose homeostasis. Patients with Type 1 and Type 2 diabetes have impaired glycemic control due, in part, to dysregulation of the opposing actions of these hormones. While hyperglucagon ... Full text Link to item Cite

Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.

Journal Article FASEB J · May 2014 Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake an ... Full text Open Access Link to item Cite

Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice.

Journal Article Hepatology · April 2014 UNLABELLED: Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the majo ... Full text Link to item Cite

Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance.

Journal Article PLoS One · 2014 Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has been shown to have anti-inflammatory, anti-cancer, anti-steatotic effects on the liver. Autophagy also mediates similar effects; however, it is not currently known whether EGCG can ... Full text Link to item Cite

β-Adrenergic agonist and antagonist regulation of autophagy in HepG2 cells, primary mouse hepatocytes, and mouse liver.

Journal Article PLoS One · 2014 Autophagy recently has been shown to be involved in normal hepatic function and in pathological conditions such as non-alcoholic fatty liver disease. Adrenergic signalling also is an important regulator of hepatic metabolism and function. However, currentl ... Full text Link to item Cite

Resveratrol induces insulin gene expression in mouse pancreatic α-cells.

Journal Article Cell Biosci · December 13, 2013 BACKGROUND: Type 1 and type 2 diabetes are characterized by loss of β-cells; therefore, β-cell regeneration has become one of the primary approaches to diabetes therapy. Resveratrol, a naturally occurring polyphenolic compound, has been shown to improve gl ... Full text Link to item Cite

Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells.

Journal Article Biochem Biophys Res Commun · November 1, 2013 Thyroid hormones (THs) regulate transcription of many metabolic genes in the liver through its nuclear receptors (TRs). Although the molecular mechanisms for positive regulation of hepatic genes by TH are well understood, much less is known about TH-mediat ... Full text Link to item Cite

FoxO1 deacetylation regulates thyroid hormone-induced transcription of key hepatic gluconeogenic genes.

Journal Article J Biol Chem · October 18, 2013 Hepatic gluconeogenesis is a concerted process that integrates transcriptional regulation with hormonal signals. A major regulator is thyroid hormone (TH), which acts through its nuclear receptor (TR) to induce the expression of the hepatic gluconeogenic g ... Full text Link to item Cite

PI3K stimulates DNA synthesis and cell-cycle progression via its p55PIK regulatory subunit interaction with PCNA.

Journal Article Mol Cancer Ther · October 2013 Previously, we have shown that p55PIK, an isoform of class I(A) phosphoinositide 3-kinase (PI3K), specifically interacts with important cell-cycle regulators, such as retinoblastoma (Rb), to promote cell-cycle progression. Here, we used the glutathione S-t ... Full text Link to item Cite

Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library.

Journal Article BMC Med Genomics · August 9, 2012 BACKGROUND: While there is strong evidence for phosphatidylinositol 3-kinase (PI3K) involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene that encodes the PI3K regulatory subunit p55γ, ... Full text Link to item Cite

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy.

Journal Article J Clin Invest · July 2012 For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is kno ... Full text Link to item Cite

Thyroid Disorders

Chapter · March 27, 2012 Cite

Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism.

Journal Article Cell · August 19, 2011 The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living cells indicate that receptors transiently interact with D ... Full text Link to item Cite

Distinct and histone-specific modifications mediate positive versus negative transcriptional regulation of TSHalpha promoter.

Journal Article PLoS One · March 24, 2010 BACKGROUND: Hormonally-regulated histone modifications that govern positive versus negative transcription of target genes are poorly characterized despite their importance for normal and pathological endocrine function. There have been only a few studies e ... Full text Link to item Cite

Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.

Journal Article J Am Chem Soc · March 10, 2010 LSD1 is a flavin-dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to imines that are hydrolytically cleave ... Full text Link to item Cite

Negative regulation of TSHalpha target gene by thyroid hormone involves histone acetylation and corepressor complex dissociation.

Journal Article Mol Endocrinol · May 2009 Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T(3)) decreased transcription, and surprisingly increased histone acetylation, of TSHalpha promoter. ... Full text Link to item Cite

Thyroid Hormone Action

Journal Article · January 1, 2009 Full text Cite

A peptide inhibitor derived from p55PIK phosphatidylinositol 3-kinase regulatory subunit: a novel cancer therapy.

Journal Article Mol Cancer Ther · December 2008 p55PIK, a regulatory subunit of phosphatidylinositol 3-kinase (PI3K), specifically interacts with retinoblastoma protein (Rb) through the unique NH2 terminus of p55PIK, N24. This interaction is critical for cell proliferation and cell cycle progression. To ... Full text Link to item Cite

New insights into thyroid hormone action.

Journal Article Best Pract Res Clin Endocrinol Metab · June 2007 Thyroid hormones (THs) have important effects on cellular development, growth, and metabolism. They bind to thyroid hormone receptors (TRs), TRalpha and TRbeta, which belong to the nuclear hormone receptor superfamily. These receptors also bind to enhancer ... Full text Link to item Cite

The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions.

Journal Article Endocrinology · April 2007 The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors ... Full text Link to item Cite

Thyroid hormone-regulated target genes have distinct patterns of coactivator recruitment and histone acetylation.

Journal Article Mol Endocrinol · March 2006 Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase ... Full text Link to item Cite

Thyroid hormone action at the cellular, genomic and target gene levels.

Journal Article Mol Cell Endocrinol · February 26, 2006 Thyroid hormone (TH) plays important roles in metabolism, growth and differentiation. Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors that bind both TH and DNA enhancer sequences in the promoter region of target genes where the ... Full text Link to item Cite

Protein synthesis inhibitors and the chemical chaperone TMAO reverse endoplasmic reticulum perturbation induced by overexpression of the iodide transporter pendrin.

Journal Article J Cell Sci · April 15, 2005 An outcome of overloading of the endoplasmic reticulum (ER) folding machinery is a perturbation in ER function and the formation of intracellular aggregates. The latter is a key pathogenic factor in numerous diseases known as ER storage diseases. Here, we ... Full text Link to item Cite

p62, A TFIIH subunit, directly interacts with thyroid hormone receptor and enhances T3-mediated transcription.

Journal Article Mol Endocrinol · April 2005 Currently, little is known about the direct interactions of general transcription factors and nuclear hormone receptors. To investigate the potential role of the general transcription factor, TFIIH, in T3-mediated transcriptional activation, we examined th ... Full text Link to item Cite

Graves' disease after interleukin-2 therapy in a patient with human immunodeficiency virus infection.

Journal Article Thyroid · December 2004 Interleukin-2 (IL-2) is a cytokine that regulates the proliferation and differentiation of lymphocytes, and is currently used clinically in the treatment of assorted malignancies. Additionally, IL-2 is being actively investigated in clinical trials for tre ... Full text Link to item Cite

Cell cycle-dependent expression of thyroid hormone receptor-beta is a mechanism for variable hormone sensitivity.

Journal Article Mol Biol Cell · April 2004 Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors. Currently, little is known about the expression of TRs or other nuclear hormone receptors during the cell cycle. We thus developed a stable expression system to express green flu ... Full text Link to item Cite

Molecular basis of resistance to thyroid hormone.

Journal Article Trends Endocrinol Metab · September 2003 Resistance to thyroid hormone (RTH) is a syndrome in which patients have raised serum thyroid hormone (TH) levels and raised or inappropriately normal thyrotropin (TSH) levels. In general, patients exhibit TH resistance in the pituitary and peripheral tiss ... Full text Link to item Cite

Germline and somatic thyroid hormone receptor mutations in man.

Journal Article J Endocrinol Invest · August 2003 Thyroid hormone plays important roles in metabolism, growth, and differentiation. Germline mutations in thyroid hormone receptor beta (TRbeta) have been identified in many individuals with resistance to thyroid hormone (RTH), a syndrome of hyposensitivity ... Full text Link to item Cite

Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice.

Journal Article EMBO Rep · June 2003 Little is known about the overall patterns of thyroid hormone (Th)-mediated gene regulation by the main Th receptor (Tr) isoforms, Tr-alpha and Tr-beta, in vivo. We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wild-t ... Full text Link to item Cite

Dynamic shuttling and intranuclear mobility of nuclear hormone receptors.

Journal Article J Biol Chem · April 4, 2003 We expressed green fluorescent protein (GFP) chimeras of estrogen, retinoic acid, and thyroid hormone receptors (ERs, RARs, and TRs, respectively) in HeLa cells to examine nucleocytoplasmic shuttling and intranuclear mobility of nuclear hormone receptors ( ... Full text Link to item Cite

Microarray analysis of knockout mice identifies cyclin D2 as a possible mediator for the action of thyroid hormone during the postnatal development of the cerebellum.

Journal Article Dev Biol · February 15, 2003 Thyroid hormone is a major regulator of postnatal brain development, but the precise molecular mechanisms underlying its action in this organ remain poorly understood. We used microarray analysis to identify new target genes in brain. Thyroid hormone treat ... Full text Link to item Cite

Role of the asialoglycoprotein receptor in binding and entry of hepatitis C virus structural proteins in cultured human hepatocytes.

Journal Article J Virol · January 2003 We used a baculovirus-based system to prepare structural proteins of hepatitis C virus (HCV) genotype 1a. Binding of this preparation to cultured human hepatic cells was both dose dependent and saturable. This binding was decreased by calcium depletion and ... Full text Link to item Cite

Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome.

Journal Article Hum Mol Genet · October 1, 2002 Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with th ... Full text Link to item Cite

Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations.

Journal Article Thyroid · January 2002 Resistance to thyroid hormone (RTH) is a clinical syndrome characterized by elevated serum thyroid hormone (TH) levels, unsuppressed thyrotropin (TSH) levels, and tissue hyposensitivity to TH. In almost all cases, the genetic basis of RTH lies in mutation ... Full text Link to item Cite

Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant.

Journal Article J Clin Endocrinol Metab · November 2001 Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH w ... Full text Link to item Cite

Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor.

Journal Article J Clin Endocrinol Metab · November 2001 In patients with TSH-secreting tumors (TSHomas), serum TSH is poorly suppressed by thyroid hormone. The mechanism for this defect in negative regulation of TSH secretion is not known. To investigate the possibility of a somatic mutation of TR causing this ... Full text Link to item Cite

Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance.

Journal Article Mol Endocrinol · September 2001 Patients with TSH-secreting pituitary tumors (TSHomas) have high serum TSH levels despite elevated thyroid hormone levels. The mechanism for this defect in the negative regulation of TSH secretion is not known. We performed RT-PCR to detect mutations in TR ... Full text Link to item Cite

Physiological and molecular basis of thyroid hormone action.

Journal Article Physiol Rev · July 2001 Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor su ... Full text Link to item Cite

Transgenic targeting of a dominant negative corepressor to liver blocks basal repression by thyroid hormone receptor and increases cell proliferation.

Journal Article J Biol Chem · May 4, 2001 Unliganded thyroid hormone receptors (TRs) interact with corepressors and repress basal transcription of target genes in cotransfection and in vitro studies. Currently, little is known about the function of corepressors in vivo. We thus used a mouse albumi ... Full text Link to item Cite

A case of spurious hypercalcitoninemia: a cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia.

Journal Article J Endocrinol Invest · May 2001 The measurement of plasma CT has an important role as a screening test for medullary thyroid carcinoma (MTC) in patients with thyroid nodules. However, elevated plasma CT levels should be interpreted within the context of the overall clinical picture in ea ... Full text Link to item Cite

Nuclear cytoplasmic shuttling by thyroid hormone receptors. multiple protein interactions are required for nuclear retention.

Journal Article J Biol Chem · April 6, 2001 In this report, we have studied the intracellular dynamics and distribution of the thyroid hormone receptor-beta (TRbeta) in living cells, utilizing fusions to the green fluorescent protein. Wild-type TRbeta was mostly nuclear in both the absence and prese ... Full text Link to item Cite

The glucocorticoid receptor interacting protein 1 (GRIP1) localizes in discrete nuclear foci that associate with ND10 bodies and are enriched in components of the 26S proteasome.

Journal Article Mol Endocrinol · April 2001 The glucocorticoid receptor interacting protein-1 (GRIP1) is a member of the steroid receptor coactivator (SRC) family of transcriptional regulators. Green fluorescent protein (GFP) fusions were made to full-length GRIP1, and a series of GRIP1 mutants lack ... Full text Link to item Cite

Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray.

Journal Article Mol Endocrinol · July 2000 The liver is an important target organ of thyroid hormone. However, only a limited number of hepatic target genes have been identified, and little is known about the pattern of their regulation by thyroid hormone. We used a quantitative fluorescent cDNA mi ... Full text Link to item Cite

Recombinant human thyrotropin for the diagnosis and treatment of a highly functional metastatic struma ovarii.

Journal Article J Clin Endocrinol Metab · January 2000 The optimal treatment of metastatic thyroid cancer that produces high amounts of thyroid hormone has not been well defined. A 46-yr-old woman presented with a follicular thyroid carcinoma arising from a struma ovarii with hepatic metastases. After the remo ... Full text Link to item Cite

Thyrotropin receptor mutations in thyroid diseases.

Journal Article Rev Endocr Metab Disord · January 2000 Full text Link to item Cite

Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene.

Journal Article EMBO J · October 1, 1999 We have investigated ligand-dependent negative regulation of the thyroid-stimulating hormone beta (TSHbeta) gene. Thyroid hormone (T3) markedly repressed activity of the TSHbeta promoter that had been stably integrated into GH(3 )pituitary cells, through t ... Full text Link to item Cite

Human trabecular meshwork cells as a thyroid hormone target tissue: presence of functional thyroid hormone receptors.

Journal Article Graefes Arch Clin Exp Ophthalmol · March 1999 PURPOSE: To determine whether human trabecular meshwork cells (HTM) are a potential target tissue for thyroid hormone (3,3',5-triiodothyronine, T3). METHODS: Cultured HTM were assayed for the presence of thyroid hormone receptors (TRs) and retinoid X recep ... Full text Link to item Cite

ROR alpha augments thyroid hormone receptor-mediated transcriptional activation.

Journal Article Endocrinology · March 1999 This study is designed to clarify the role of an orphan nuclear hormone receptor, ROR alpha, on thyroid hormone (TH) receptor (TR)-mediated transcription on a TH-response element (TRE). A transient transfection study using various TREs [i.e., F2 (chick lys ... Full text Link to item Cite

Recent advances in understanding thyroid hormone receptor coregulators.

Journal Article J Biomed Sci · 1999 Thyroid hormones (L-triiodothyronine, T3; L-tetraiodothyronine, T4) regulate normal cellular growth and development, and general metabolism as well. Their various actions are mediated by the thyroid hormone receptor, a ligand-dependent transcriptional fact ... Full text Link to item Cite

Intracellular proteolytic cleavage of 9-cis-retinoic acid receptor alpha by cathepsin L-type protease is a potential mechanism for modulating thyroid hormone action.

Journal Article J Biol Chem · December 11, 1998 We previously reported that the responsiveness of hepatocytes to thyroid hormone is markedly attenuated when they were cultured as monolayers rather than spheroids. To elucidate the mechanisms underlying the altered responsiveness, thyroid hormone receptor ... Full text Link to item Cite

Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors.

Journal Article Endocrinology · October 1998 We studied the interactions of two natural thyroid hormone receptor (TR) mutants from patients with resistance to thyroid hormone (RTH) and an artificial TR mutant with a nuclear receptor corepressor, N-CoR, and a steroid receptor coactivator, SRC-1. In el ... Full text Link to item Cite

Thyroid hormone response elements differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor coactivator-1.

Journal Article J Biol Chem · August 21, 1998 Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). ... Full text Link to item Cite

Expression and hormonal regulation of coactivator and corepressor genes.

Journal Article Endocrinology · May 1998 Steroid/thyroid/retinoid receptors are members of the nuclear receptor superfamily and ligand-inducible transcription factors. These receptors modulate transcription of various cellular genes, either positively or negatively, by interacting with specific h ... Full text Link to item Cite

An inhibitory region of the DNA-binding domain of thyroid hormone receptor blocks hormone-dependent transactivation.

Journal Article Mol Endocrinol · January 1998 We have employed a chimeric receptor system in which we cotransfected yeast GAL4 DNA-binding domain/retinoid X receptor beta ligand-binding domain chimeric receptor (GAL4RXR), thyroid hormone receptor-beta (TRbeta), and upstream activating sequence-reporte ... Full text Link to item Cite

Species differences in cardiac thyroid hormone receptor isoforms protein abundance.

Journal Article Biol Pharm Bull · November 1997 Little is known about the cardiac expression of different thyroid hormone receptor (TR) isoforms. The aim of the study was to investigate such patterns of TR expression at the protein level in different species and in some human tissues. Western blot analy ... Full text Link to item Cite

Interactions of estrogen- and thyroid hormone receptors on a progesterone receptor estrogen response element (ERE) sequence: a comparison with the vitellogenin A2 consensus ERE.

Journal Article Mol Endocrinol · October 1997 The identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the half-site of the estrogen-response element (ERE) and a consensus sequence constituting the thyroid hormone- ... Full text Link to item Cite

Protein synthesis-dependent potentiation by thyroxine of antiviral activity of interferon-gamma.

Journal Article Am J Physiol · October 1997 We have studied the prenuclear signal transduction pathway by which thyroid hormone potentiates the antiviral activity of human interferon-gamma (IFN-gamma) in HeLa cells, which are deficient in thyroid hormone receptor (TR). The action of thyroid hormone ... Full text Link to item Cite

Immunohistochemical expression of retinoid X receptor isoforms in human pituitaries and pituitary adenomas.

Journal Article Neuroendocrinology · April 1997 Retinoid X receptors (RXRs) are transcriptional factors that belong to the steroid/thyroid hormone receptor superfamily. There are 3 RXR isoforms-alpha, beta, gamma-known to bind 9-cis-retinoic acid as their ligand. The expression of RXRs in human pituitar ... Full text Link to item Cite

Mutant and wild-type androgen receptors exhibit cross-talk on androgen-, glucocorticoid-, and progesterone-mediated transcription.

Journal Article Mol Endocrinol · February 1997 Androgen, glucocorticoid, and progesterone receptors (ARs, GRs, and PRs) often can regulate transcription via composite hormone response elements in target genes. We have used artificial and natural mutant ARs from patients with androgen resistance to stud ... Full text Link to item Cite

Estrogen and thyroid hormone interaction on regulation of gene expression.

Journal Article Proc Natl Acad Sci U S A · October 29, 1996 Estrogen receptor (ER) and thyroid hormone receptors (TRs) are ligand-dependent nuclear transcription factors that can bind to an identical half-site, AGGTCA, of their cognate hormone response elements. By in vitro transfection analysis in CV-1 cells, we s ... Full text Link to item Cite

The peroxisome proliferator-activated receptor alpha is a phosphoprotein: regulation by insulin.

Journal Article Endocrinology · October 1996 Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily implicated in adipocyte differentiation. The observations that PPAR alpha is a regulator of hepatic lipid metabolism and that the insulin-sensitizin ... Full text Link to item Cite

Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator.

Journal Article Endocrinology · August 1996 Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that regulate target gene transcription. The conserved carboxy-terminal region of the ligand-binding domain (AF-2) has been thought to play a critical role in mediating ligand-depen ... Full text Link to item Cite

Vitamin D receptors repress basal transcription and exert dominant negative activity on triiodothyronine-mediated transcriptional activity.

Journal Article J Biol Chem · May 3, 1996 We have examined vitamin D receptor (VDR), thyroid hormone receptor (TR), and retinoid X receptor beta (RXR beta) binding to vitamin D response elements (VDREs), two thyroid hormone response elements (TREs) (DR4 and F2), and a retinoic acid response elemen ... Full text Link to item Cite

The isoform-specific expression of the tri-iodothyronine receptor in osteoblasts and osteoclasts.

Journal Article Eur J Clin Invest · May 1996 Hyperthyroidism is associated with an increase in both osteoblast and osteoclast activity. We have previously shown that, in vitro, osteoclasts do not respond directly to tri-iodothyronine to increase bone resorption but that the effect is mediated by anot ... Full text Link to item Cite

Milrinone mimics thyroid hormone potentiation of the antiviral activity of human interferon-γ in hela cells

Journal Article Journal of Investigative Medicine · January 1, 1996 Milrinone (Mil) is a bipyridine inotropic agent which has structural homologies with thyroid hormone and thyromimetic effects in several tissues. We have examined the action of Mil and amrinone (Am) in a system in which Lthyroxine (T4) and 3,5,3'-triiodo-L ... Cite

Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors?

Journal Article J Clin Endocrinol Metab · November 1995 Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone, is linked to mutations in the thyroid hormone receptor-beta (TR beta) gene. The purpose of this study was to determine whether the clinical ... Full text Link to item Cite

Factors that enhance Escherichia coli-expressed TR beta binding to T3 and DNA.

Journal Article Thyroid · August 1995 Thyroid hormone receptors (TRs) recently have been produced in E. coli by several laboratories. We produced E. coli-expressed human TR beta using the histidine/fusion protein system. Surprisingly, we observed that reticulocyte lysate, nonspecific proteins, ... Full text Link to item Cite

Studies on the repression of basal transcription (silencing) by artificial and natural human thyroid hormone receptor-beta mutants.

Journal Article Endocrinology · July 1995 Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that regulate target gene transcription. Interestingly, in the absence of ligand, TRs also can repress basal transcription of positively regulated target genes, suggesting that unli ... Full text Link to item Cite

Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland.

Journal Article Endocrinology · April 1995 There are three known isoforms of the retinoid-X receptor (RXR): RXR alpha, RXR beta, and RXR gamma. RXR alpha and RXR beta messenger RNAs are widely expressed, whereas RXR gamma messenger RNA is restricted to only a few tissues, including embryonic pituit ... Full text Link to item Cite

Steroid hormone receptors selectively affect transcriptional activation but not basal repression by thyroid hormone receptors.

Journal Article Endocrinology · February 1995 Thyroid hormone receptors (TRs) and steroid hormone receptors belong to a large superfamily of nuclear hormone receptors. The interactions between these receptor subfamilies are poorly understood. In this study, cotransfection assays were used to examine t ... Full text Link to item Cite

9-cis retinoic acid regulation of rat growth hormone gene expression: potential roles of multiple nuclear hormone receptors.

Journal Article Endocrinology · November 1994 Rat GH (rGH) gene expression is increased by both thyroid hormone (T3) and all-trans retinoic acid (RA) via a composite hormone response element (HRE) containing three putative half-sites (rGH-HRE). However, it is not known whether 9-cis RA (9cRA) also can ... Full text Link to item Cite

Heterodimerization and deoxyribonucleic acid-binding properties of a retinoid X receptor-related factor.

Journal Article Endocrinology · November 1994 The extent thyroid hormone receptors (TRs) bind to AGGTCA-related motifs as monomers and/or homodimers, and as heterodimers with retinoid X receptors (RXRs) depends on the number, spacing, and orientation of these half-sites. Here we show that recombinant ... Full text Link to item Cite

Differential expression of thyroid hormone receptor isoforms in neurons and astroglial cells.

Journal Article Endocrinology · August 1994 The brain has abundant nuclear T3-binding sites and contains messenger RNAs (mRNAs) encoding multiple thyroid hormone receptor (TR) isoforms; the cellular distribution of these different TR isoforms is unknown. To determine whether the TR isoforms are diff ... Full text Link to item Cite

Half-site arrangement of hybrid glucocorticoid and thyroid hormone response elements specifies thyroid hormone receptor complex binding to DNA and transcriptional activity.

Journal Article J Biol Chem · April 29, 1994 Thyroid hormone receptors bind to thyroid hormone response elements (TREs) as heterodimers with 3,5,3'-L-triiodothyronine (T3) receptor auxiliary protein (TRAP) and retinoid X receptors (RXRs). Currently, it is not known whether TR/TRAP or TR/RXR heterodim ... Link to item Cite

Roles of 3,5,3'-triiodothyronine and deoxyribonucleic acid binding on thyroid hormone receptor complex formation.

Journal Article Endocrinology · March 1994 Thyroid hormone receptors (TRs) bind to thyroid hormone response elements (TREs) in the promoter region of target genes as monomers, homodimers, and heterodimers with nuclear proteins such as retinoid-X receptors (RXRs). Recently, we observed that T3 decre ... Full text Link to item Cite

In vitro transcriptional studies of the roles of the thyroid hormone (T3) response elements and minimal promoters in T3-stimulated gene transcription.

Journal Article J Biol Chem · January 14, 1994 Thyroid hormone receptors (TRs) are ligand-dependent nuclear transcription factors that are encoded by two different genes, TR alpha and TR beta, and bind to thyroid hormone response elements (TREs) in the promoters of thyroid hormone (T3)-regulated genes. ... Link to item Cite

Roles of v-erbA homodimers and heterodimers in mediating dominant negative activity by v-erbA.

Journal Article J Biol Chem · January 14, 1994 v-erbA, a viral oncogenic homolog of thyroid hormone receptor (TR), blocks the effect of T3 in TR-mediated transcription. The mechanism(s) for this dominant negative effect by v-erbA on TRs is unknown but may involve competition between v-erbA and TR-conta ... Link to item Cite

Phosphorylation selectively increases triiodothyronine receptor homodimer binding to DNA.

Journal Article J Biol Chem · January 7, 1994 Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements (TREs) as monomers and homodimers, and as heterodimers with nuclear proteins such as TR auxiliary proteins and retinoid X receptors. R ... Link to item Cite

New advances in understanding the molecular mechanisms of thyroid hormone action

Journal Article Trends in Endocrinology and Metabolism · January 1, 1994 Thyroid hormone regulation o f gene transcription is a complex process. There are multiple thyroid hormone receptors (TRs) encoded on separate genes that bind to thyroid hormone-response elements (TREs) of target genes containing different orientation and ... Full text Cite

Region-specific anti-thyroid hormone receptor (TR) antibodies detect changes in TR structure due to ligand-binding and dimerization.

Journal Article Mol Cell Endocrinol · November 1993 There are multiple factors that potentially can induce structural changes in DNA-bound thyroid hormone receptors (TRs) including protein-protein interactions, ligand-binding to TRs, and the thyroid hormone response element (TRE) sequence. We used a battery ... Full text Link to item Cite

Characterization and tissue expression of multiple triiodothyronine receptor-auxiliary proteins and their relationship to the retinoid X-receptors.

Journal Article Endocrinology · September 1993 Thyroid hormone receptor (TR) binding to thyroid hormone response elements is enhanced by heterodimerization with T3 receptor auxiliary proteins (TRAPs). Although retinoid X-receptors (RXRs) behave similarly to TRAP by heterodimerizing with TRs and enhanci ... Full text Link to item Cite

Glucocorticoid receptor binding to rat liver nuclei occurs without nuclear transport.

Journal Article J Steroid Biochem Mol Biol · September 1993 The binding of cell-free activated glucocorticoid receptor-steroid complexes from HTC cells to various preparations of HTC and rat liver nuclei has been examined under conditions that did or did not support the nuclear translocation of macromolecules via n ... Full text Link to item Cite

Different dimerization activities of alpha and beta thyroid hormone receptor isoforms.

Journal Article J Biol Chem · May 15, 1993 Thyroid hormone receptors (TR) are ligand-dependent transcription factors that are encoded as multiple isoforms on two genes. To date, no functional differences have been shown between the TR isoforms; however, the maintenance of alpha and beta genes durin ... Link to item Cite

Triiodothyronine (T3) differentially affects T3-receptor/retinoic acid receptor and T3-receptor/retinoid X receptor heterodimer binding to DNA.

Journal Article J Biol Chem · November 15, 1992 Thyroid hormone receptor (TR) heterodimerizes with retinoic acid receptor (RAR), retinoid X receptor (RXR), and triiodothyronine receptor auxiliary protein (TRAP) on natural and synthetic hormone response elements. Recently we showed that triiodothyronine ... Link to item Cite

New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.

Journal Article J Clin Invest · November 1992 Generalized resistance to thyroid hormone (GRTH) is a syndrome of hyposensitivity to triiodothyronine (T3) that displays autosomal dominant inheritance. The genetic defect commonly lies in the ligand-binding domain of one of the TR beta alleles. Since ther ... Full text Link to item Cite

Isoform-specific thyroid hormone receptor antibodies detect multiple thyroid hormone receptors in rat and human pituitaries.

Journal Article Endocrinology · March 1992 There are three known isoforms of the thyroid hormone receptor (TR) in the rat: TR alpha-1, TR beta-1, and TR beta-2. The TR alpha-1 and TR beta-1 mRNAs are found in many tissues, whereas TR beta-2 mRNA is detected only in the pituitary gland. Thus far, TR ... Full text Link to item Cite

Triiodothyronine (T3) decreases binding to DNA by T3-receptor homodimers but not receptor-auxiliary protein heterodimers.

Journal Article J Biol Chem · February 25, 1992 Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that bind to thyroid hormone response elements (TREs) to mediate positive and negative regulation of transcription of thyroid hormone-responsive genes. TR binding to TREs can be enh ... Link to item Cite

Basal and thyroid hormone receptor auxiliary protein-enhanced binding of thyroid hormone receptor isoforms to native thyroid hormone response elements.

Journal Article Endocrinology · December 1991 There are three known isoforms of the rat thyroid hormone receptor, TR alpha-1, TR beta-1, and TR beta-2. The first two are expressed in all tissues, whereas TR beta-2 appears to be expressed only in the pituitary. The differences in the roles of the three ... Full text Link to item Cite

Evidence against posttranslational glycosylation of rat glucocorticoid receptors.

Journal Article Receptor · 1991 The observed M(r) of the rat glucocorticoid receptor on denaturing polyacrylamide gels is 7-11 kDa higher than that deduced from the cloned cDNA sequence of the receptor. Posttranslational modification of the receptor, such as glycosylation, could account ... Link to item Cite

Differential modulation of gene induction by glucocorticoids and antiglucocorticoids in rat hepatoma tissue culture cells.

Journal Article Cancer Res · April 15, 1989 Studies of glucocorticoid and antiglucocorticoid induction of tyrosine aminotransferase (TAT) in two rat hepatoma cell lines (Fu5-5 and HTC) are described. These studies revealed several phenomena that are not consistent with the current models of steroid ... Link to item Cite

Region-specific antiglucocorticoid receptor antibodies selectively recognize the activated form of the ligand-occupied receptor and inhibit the binding of activated complexes to deoxyribonucleic acid.

Journal Article Mol Endocrinol · February 1989 A synthetic 18-amino acid peptide (Cys500-Lys517) was used to raise polyclonal antibodies in rabbits to the glucocorticoid receptor (GR). The sequence of this peptide is identical to that of residues 500-517 of the rat and 481-498 of the human GR. This seq ... Full text Link to item Cite

Short chain fatty acids increase prolactin and growth hormone production and alter cell morphology in the GH3 strain of rat pituitary cells.

Journal Article Endocrinology · July 1981 Treatment of GH3 cells for 24-72 h with sodium valerate (1 mM) increased 2- to 4-fold the production of both PRL and GH. There was a concomitant change in the morphology of the cells that resembled that produced by TRH and epidermal growth factor. The incr ... Full text Link to item Cite

Anti-estrogenic compounds increase prolactin and growth hormone synthesis in clonal strains of rat pituitary cells.

Journal Article Endocrinology · October 1977 Established clonal strains of rat pituitary cells, GH-cells, responded prior to 1974 to 10(-11) to 10(-8)M 17beta-estradiol by increasing prolactin synthesis 2-fold and decreasing the production of growth hormone to between 20 and 70% of control values. In ... Full text Link to item Cite