Thyroid Hormone Receptor Beta Research Articles

A Case of Thyroid Hormone Resistance Syndrome with a Novel Mutation (c.947G>a) in the THRB Gene: Experience in Diagnosis and Treatment

A Case of Thyroid Hormone Resistance Syndrome with a Novel Mutation (c.947G>a) in the THRB Gene: Experience in Diagnosis and Treatment

8507 Misdiagnosis of Graves’ and RAI Treatment in Patient with THRB Gene Mutation

Abstract Disclosure: E. McBride: None. R. Kennedy: None. A.N. Davis: None. S.J. Healy: None. Introduction: Resistance to thyroid hormone (RTH) is an inherited condition in which there is decreased tissue responsiveness to thyroid hormone. Occasionally patients with this condition can be misdiagnosed with hyperthyroidism.Clinical case: A 35 yo female was referred to our clinic for evaluation of postablative hypothyroidism. 6 years prior, the patient was evaluated by endocrinology at our city’s army hospital. The patient had abnormal TFTs during HTN workup but was otherwise asymptomatic. Family history included goiter in paternal aunt and grandmother (s/p thyroidectomy). Labs showed TSH 0.370 mIU/L (0.3-3); FT4 2.01, repeat 1.96 ng/dl (0.6-1.6); FT3 6.10 pg/ml (2.3-4.4); T4 16.2 mcg/dl (4.5-12); alpha subunit 0.32ng/ml; TBG 31 mcg/ml (13-39). On exam patient had thyromegaly. Thyroid US showed normal gland with length 5.6 cm. Subsequent labs showed negative thyroglobulin ab, antithyroid microsomal ab, TBII, and TSI. Resistance to thyroid hormone (RTH) was suspected. Pt underwent RTH mutation analysis. Result was heterozygous for c.715T>A (pTrp239Arg) in exon 7 of the THRB gene, described as variant of unknown significance. Treatment was not recommended. Patient desired pregnancy and was evaluated by our hospital’s MFM clinic for preconception counseling. Per notes, patient had another child who tested negative for the gene.Patient then moved out of state, and 1 year later she underwent ablation for presumed diagnosis of Graves’ disease. The records from that hospital are not available. Patient later moved back to our city and was evaluated in clinic. At that visit, weight was 44 kg and patient was on 200 mcg LT4 daily. Pt endorsed cold intolerance, mood swings, brain fog, some hair loss. Recent thyroid US showed diminutive thyroid, and outside labs showed TSH 7.288, TPO ab <4. Our labs showed TSH 8.6 and FT4 2.05. Pt was still interested in becoming pregnant. She did not recall the prior genetic testing or diagnosis of RTH, and believed that she had Graves’. Patient did not return for follow up visit and later moved out of state.Conclusions: Patient’s labs showed elevated T4 and T3 with normal TSH. Genetic testing revealed a mutation in THRB gene. The normal codon is TGG coding for tryptophan and mutation in this patient is AGG coding for arginine. Other mutations in this same codon result in reduced T3 binding affinity.This patient was later was misdiagnosed as having Graves’ at an outside hospital, presumably due to labs and increased thyroid uptake. Patient underwent unnecessary RAI treatment. It is common for these patients to require higher than expected doses of thyroid hormone.This case illustrates the importance of obtaining outside records and correlating thyroid function tests with imaging studies. It is a reminder that not all cases of increased thyroid uptake are due to Graves’. Management of thyroid hormone can be challenging in patients with RTH who have undergone ablation. Presentation: 6/3/2024

8747 A Rare Receptor Resistance with Paradoxical Outcomes!

Abstract Disclosure: I. Patoli: None. S. Batool: None. A.S. Gill: None. A. Makdissi: None. Introduction: Resistance to thyroid hormone receptor is an uncommon cause of abnormal TFTs. (1) We present an interesting case of THRB resistance with cardiac arrhythmia (CA). Clinical Case: 46-year-old man with history of atrial fibrillation (Afib) was referred to endocrinology for evaluation of abnormal TFTs and thyroid nodule. He had a recent hospital admission for Afib with rapid ventricular response; 3 years ago, he was treated with amiodarone for 2 months. TFTs revealed normal TSH of 1.375, elevated FT4 of 2.76 (normal ranges 0.55-4.78 and 0.89-1.76, respectively). Neck CT scan showed large peripherally enhancing centrally necrotic mass with calcification encompassing nearly the entirety of left thyroid lobe measuring 2.2 x 3.6 x 4.6 cm. A 0.8 cm hypodensity within right thyroid lobe also visualized. Thyroid ultrasound showed nodules bilaterally with the largest one in the lower pole of left lobe. FNA biopsy showed Bethesda category- II benign, benign appearing follicular cells and abundant colloid. Repeat labs showed similar results with persistently elevated free T4 (2.56) with equilibrium dialysis, normal alpha subunit, normal TSH (2.14) with human anti-mouse antibody (HAMA) antibody was negative. Alpha subunit:TSH ratio was <1. He remained clinically euthyroid over the course of 1.5 year but repeat labs at that time indicated that TSH had increased to 17 with elevated free T4 (2.6) . MRI brain ruled out TSH secreting adenoma. He reported thyroid abnormalities in son and brother but was unable to provide details. He was referred for genetic screening which showed THRB with pathogenic variant: c.9628> G (p.Y321C). Conclusion: THRB resistance is an uncommonly diagnosed modality in endocrinology. The genes encoding thyroid hormone receptors are THRα gene and THRβ gene (2). Patients with inherited THRB pathogenic variants present with resistance to thyroid hormone and often enlarged thyroid gland. Interestingly, despite having receptor resistance, patients may manifest with CA. This is hypothesized to be due to elevated T4 and T3 concentration in the heart which primarily has higher expression of THRA (3). The diagnosis of thyroid hormone resistance is important to avoid treating asymptomatic patients where treatment is not warranted.

7885 Thyroid Hormone Stimulates Heaptic Lipid Metabolism in the Resolution of Liver Fibrosis

Abstract Disclosure: A. Mendoza: None. C. Wang: None. A. Lugo: None. V. Rodrigues: None. S. Houghton: None. D. Redmond: None. A. Hollenberg: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis and fibrosis is a global health burden, leading to liver failure and death. While the pathogenesis is complex, dysregulated lipid metabolism plays a crucial role. Thyroid hormones (THs) are key metabolic regulators in the liver, promoting lipogenesis and fatty acid oxidation. Previously, we demonstrated that the carbohydrate-responsive element binding protein (ChREBP) is a critical mediator of both these processes in hepatocytes, acting downstream of the thyroid hormone receptor beta1 (TRβ1). Interestingly, while ChREBP ablation abolished TH-induced lipogenesis through downregulation of lipogenic gene expression, its role in TH-mediated fatty acid oxidation remained unclear, suggesting a multifaceted role for ChREBP in TH-regulated hepatic metabolism. Given the critical role of lipid metabolism in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, we aim to delineate the mechanisms by which TH promotes the regression of fibrosis. Here, we used a carbon tetrachloride (CCL4) model of liver fibrosis in TRβ1KO and ChREBPKO mice (0.4 ul/g biweekly, 9 injections). All mice in the experiments were also on a PTU-Low Iodine diet to induce hypothyroidism. In the last week of the protocol, all mice were sorted into two groups which received either water or T3 (1ug/ml). 24 hours after the last CCL4 injection all mice were sacrificed and the livers were harvested and prepared for analysis. Herein we show that T3 promotes the resolution of liver fibrosis in wild-type mice. Importantly, this resolution was abolished in both TRβ1 and ChREBP KO mice demonstrating this pathways essential role in TH-induced resolution of fibrosis. RNA-Seq analysis of TRβ1KO mice demonstrated a dual mechanism of TH action: 1. TH upregulates gene expression in multiple metabolic pathways, suggesting a rescue of hepatic metabolism towards normal liver function and 2., TH has antifibrotic action via downregulation of pathways controlling extracellular matrix synthesis and inflammation, key drivers of fibrosis. Strikingly, ChREBP was dispensable for the antifibrotic action of TH suggesting that the ChREBP-dependent regulation of hepatic metabolism is critical for the resolution of fibrosis mediated by TH. To identify novel metabolic pathways regulated by TH via ChREBP, we intersected liver mRNA-seq from TRβ1KO mice with liver-specific ChREBP Chip-Seq and identifed multiple targets regulating autophagy that require ChREBP for their activation after TH treatment. These data suggest that the ability of ChREBP to regulate TH-induced fatty-acid oxidation is mediated by the upregulation of autophagy. This supports the notion that the ability of T3 to promote the resolution of liver fibrosis is primarily dependent of it’s ability to stimulate hepatic fatty acid metabolism. Presentation: 6/1/2024

8534 Comorbid Autoimmune Thyroid Disease in a Parent-Child Pair with Resistance to Thyroid Hormone Beta

Abstract Disclosure: A.H. Smith: None. E. Grethen: None. Resistance to Thyroid Hormone Beta (RTHβ) is an inherited disorder caused by mutations in the gene encoding the thyroid hormone receptor beta protein, resulting in decreased binding affinity to triiodothyronine in certain tissues. An asymptomatic individual with RTHβ may demonstrate abnormalities in serologic evaluation of thyroid hormone markers. When other thyroid pathologies present with RTHβ, however, the diagnosis and management can quickly become complex. Below we discuss two cases, a parent-child pair, with different presentations of presumably the same RTHβ gene. Patient 1 is a 61-year-old male with a history of autoimmune thyroiditis several years ago, presenting for continuation of care; he has had levothyroxine doses gradually uptitrated to over 3 mcg/kg to normalize TSH despite persistently high free T4 levels. He also has a family history notable for six out of seven siblings with autoimmune thyroid disease. Patient 2 is a 44-year-old male who was evaluated for hypothyroidism and difficulty with levothyroxine titration. Prior to consultation, he underwent radioactive iodine ablation for presumed Grave’s disease, followed by total thyroidectomy due to persistent symptoms. Post-operatively, he required high doses of levothyroxine to maintain normal TSH levels; however T4 and T3 levels remained high. Both patients confirmed proper levothyroxine supplementation. Further analysis of both patients demonstrated mildly elevated TBG and normal alpha subunit. Patient 2 pursued genetic testing while patient 1 declined, revealing a heterozygous R320S mutation in the TR-beta protein. Further testing and genetic counseling were offered to other family members. Propranolol and levothyroxine supplementation were titrated accordingly; triiodothyronine administration was attempted but did not alleviate symptoms. These two cases demonstrate the increased risk of autoimmune thyroid disorders in patients with RTHβ and the unique challenges they pose in accurate diagnosis. Autoimmune thyroiditis in RTHβ, with goiter, elevated T4 and elevated T3 levels, can be easily confused with Grave’s disease, especially when TSH is suppressed during active thyroiditis. Timely diagnosis can aid in targeted management of sequelae, prevent ineffective treatments for comorbid conditions which may mimic other diseases, and provide anticipatory/preventive guidance for family members to help with screening. Presentation: 6/1/2024

Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes

ObjectiveThyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. MethodsTo elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions. ResultsWe found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets. ConclusionsThese results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.

Serum CD5L as potential biomarker of thyroid hormone status during pregnancy.

The thyroid hormone (TH) status is routinely assessed by thyrotropin (TSH) and thyroxine (T4). Both biomarkers are mainly regulated by TH receptor beta, whereas many peripheral organs employ the alpha receptor. Serum cluster of differentiation 5-like molecule (CD5L) is a liver-derived protein under control of both TH receptor isoforms. However, clinical data on its relation to TH status are sparse. An additional biomarker of TH status is needed in particular during pregnancy, where the routine biomarkers become dynamically disturbed. This study aimed to determine possible covariates regulating serum CD5L and to test its potential suitability as additional TH biomarker during pregnancy. A sandwich ELISA for serum CD5L was established using newly raised antibodies. Circadian effects and the impact of liver disease on serum CD5L concentrations were assessed. Serum samples from pregnant women with well-characterized TH and trace element status were analyzed, and CD5L concentrations were correlated with other indicators of TH status including TSH, fT4, fT3, copper, and selenium concentrations. The new quantitative assay for CD5L showed high accuracy. Serum CD5L was stable in dilution and refreezing experiments and did not show strong circadian variance or dependency on liver disease. In serum of pregnant women, CD5L correlated positively to fT3, but not to fT4 or TSH. Significant positive correlations of CD5L were observed with serum levels of the TH-responsive trace elements selenium and copper. The data support the potential suitability of serum CD5L as an additional marker of TH status, with potential value for pregnancy and thyroid disease.

Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis

AimsTo compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsA database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. ResultsTwenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] −51.47; 95 % confidence interval [CI]: −68.25 to −34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD −47.08; 95 % CI: −58.83 to −35.34; SUCRA 75.5), GLP-1R agonists (MD −37.36; 95 % CI: −69.52 to −5.21; SUCRA 52.3) and THR-β agonists (MD −33.20; 95 % CI: −43.90 to −22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD −9.65; 95 % CI: −19.28 to −0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD −5.79; 95 % CI: −9.50 to −2.09; SUCRA 58.2), and GLP-1RAs (MD −5.58; 95 % CI: −15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. ConclusionThese results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Increased cardiovascular morbidity and reduced life expectancy in a large Italian cohort of patients with resistance to thyroid hormone β (RTHβ).

Decreased survival and higher cardiovascular morbidity have been recently reported in a UK cohort of 61 RTHβ patients, but there is no evidence from other countries. Retrospective cohort study from an historical group of 284 Italian RTHβ patients, diagnosed between 1984 and 2023. We collected data on diagnosis of 284 cases and longitudinal data of 249 RTHβ who carried heterozygous pathogenic variants in the THRB gene. We studied how thyroid function and recognized risk factors for cardiovascular disease, such as hypertension and diabetes, affected overall mortality and major cardiovascular events. The cumulative prevalence of sinus/supraventricular tachycardia and atrial fibrillation was 40% and 18%, respectively. FT4 values 57% higher than the upper limit of normal were associated with premature cardiovascular manifestations. Major cardiovascular events (MACEs) occurred in RTHβ patients at a median age (IQR) of 59.4 years (50.4-66.4) and early mortality resulted in a mean of 11 years of life lost. While at univariable analysis hypertension, dyslipidemia, high fasting glucose/diabetes were also associated with MACEs, at multivariable analysis only age at diagnosis, increased fT4 levels, and male gender remained significantly associated with MACEs and age at diagnosis and higher fT4 levels with mortality. Previous thyroidectomy or radioiodine therapy had no statistically significant effect in the prevention of major cardiovascular events or all-cause mortality. These data should raise the general awareness on the cardiovascular risk and prompt a proactive cardiovascular monitoring in RTHβ, especially in men and those with fT4 levels above 30 pmol/L.

Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-β) Agonist for the Treatment of MASH.

Agonists of thyroid hormone receptor β (THR-β) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 (14) as a potential best in class THR-β agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates.

Epigenetic regulation of thyroid hormone action in human metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation, fibrosis, and accumulation of fatty acids in the liver. MASH disease progression has been associated with reduced thyroid hormone (TH) signaling in the liver, including reduced expression of deiodinase type I (DIO1) and TH receptor beta (THRB). However, the underlying mechanisms mediating these effects remain elusive. Here, we hypothesized that epigenetic mechanisms may be involved in modulating hepatic TH action. Liver samples from patients with and without MASH were analyzed by qRT-PCR and correlated with clinical parameters. Luciferase reporter assays and overexpression of miRNA in HepG2 cells were used to validate the functional binding of miRNA to predicted targets. DNA methylation was analyzed by bisulfite pyrosequencing. miR-34a-5p was upregulated in MASH patients and correlated positively with the clinical parameters of MASH. Using in silico and in vitro analysis, we demonstrate that miR-34a-5p is capable of targeting several modulators of local hepatic TH action, as evidenced by the functional binding of miR-34a-5p to the seed sequence in the THRB and DIO1 genes. Consequently, overexpression of miR-34a-5p in HepG2 cells reduced the expression of THRA, THRB, DIO1, and SLC10A1, thus potentially mediating an acquired hepatic resistance to TH in MASH. As an additional regulatory mechanism, DNA methylation of THRB intron 1 was increased in MASH and negatively correlated with THRB expression. miR-34a-5p constitutes a possible epigenetic master regulator of hepatic TH action, which together with THRB-specific DNA methylation could explain a possible developing TH resistance in the liver during MASH progression on the molecular level.

Thyroid hormone resistance in an infant harboring a novel de novo mutation of the thrb gene

Thyroid hormone resistance in an infant harboring a novel <i>de novo</i> mutation of the thrb gene

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THRB manipulation in fatty liver diseases.

Precision medicine and nucleotide-based therapeutics to treat MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.

Thyroid hormone receptor-beta agonist HSK31679 alleviates MASLD by modulating gut microbial sphingolipids

As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), the thyroid hormone receptor-β (THR-β) agonist MGL-3196 (resmetirom) has garnered much attention as a liver-directed, bioactive oral drug. However, studies on MGL-3196 have also identified remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation remains to be elucidated. We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied to a randomized, double-blind, placebo-controlled multiple ascending dose cohort receiving HSK31679 treatment (n= 32) or placebo (n= 8), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the multiple ascending dose cohort of HSK31679, the relative abundance of B.thetaiotaomicron was significantly enriched, impairing glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In contrast to the non-inferior effect of MGL-3196 and HSK31679 on MASH resolution in GFBTΔGCS mice, HSK31679 led to superior benefit on steatohepatitis in GFBTWT mice, due to its steric hindrance of R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. This study provided novel insights into the gut microbiota that are key to the efficacy of HSK31679 treatment, revealing microbial GCS as a potential predictive biomarker in MASH, as well as a new target for further microbiota-based treatment strategies for MASH. Remarkable heterogeneity in individual clinical efficacy of thyroid hormone receptor-β agonists and their interferences with the microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mouse models and a randomized, double-blind, multiple-dose cohort study, we identified microbial glucosylceramide synthase as a key mechanistic node in the resolution of metabolic dysfunction-associated steatohepatitis. Microbial glucosylceramide synthase activity could be a predictive biomarker of response to HSK31679 treatment or a new target for microbiota-based therapeutics in metabolic dysfunction-associated steatohepatitis.

R243W Mutation in Thyroid Hormone Resistance Syndrome Beta

A three-year-old female with a history of recurrent tonsillitis was investigated for failure to thrive and global developmental delay. Clinically, she had a triangular face with low-set ears and intermittent tachycardia. She had growth failure with her weight under the third centile while her height was within normal limits. Other systemic examinations were unremarkable. The presence of an elevated free T4 (FT4) with an inappropriately high thyroid stimulating hormone (TSH) in this patient raised the clinical suspicion of Thyroid Hormone Resistance Syndrome. DNA sequencing confirmed the diagnosis, which showed R243W gene mutation in Thyroid Hormone Receptor-Beta1 (THRB1).

Assessment of Cardiometabolic Risk Factors and Insulin Sensitivity by Hyperinsulinemic-Euglycemic Clamp in Resistance to Thyroid Hormone β Syndrome.

Background: Resistance to thyroid hormone beta (RTHβ) is a rare disease resulting from mutations in the THRB gene, characterized by reduced T3 action in tissues with high thyroid hormone receptor β expression. Thyroid hormones regulate body composition and metabolism in general, and increased or decreased hormone levels are associated with insulin resistance. This study evaluated the presence of cardiometabolic risk factors and insulin sensitivity in patients with RTHβ. Methods: In all, 16 patients, 8 adults (52.3 ± 16.3 years of age) and 8 children (10.9 ± 3.9 years of age), were compared to 28 control individuals matched for age, sex, and body mass index (BMI). Anthropometry evaluation and blood samples were collected for glycemia, lipids, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, ultrasensitive C-reactive protein (CRPus), free thyroxine, total triiodothyronine, thyrotropin, and anti-thyroid peroxidase measurements. Body composition was assessed using dual-emission X-ray absorptiometry and bioimpedance. Insulin sensitivity was evaluated in adult patients and controls using the hyperinsulinemic-euglycemic clamp (HEC), whereas homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all individuals studied. Results: Patients and controls presented similar weight, BMI, abdominal perimeter, and total fat body mass. Patients with RTHβ demonstrated higher total cholesterol (TC), p = 0.04, and low-density lipoprotein cholesterol (LDL-C), p = 0.03, but no alteration was observed in other parameters associated with metabolic risk, such as leptin, TNF-α, and CRPus. Two adult patients met the criteria for metabolic syndrome. There was no evidence of insulin resistance assessed by HEC or HOMA-IR. Elevated IL-6 levels were observed in patients with RTHβ. Conclusion: Using HEC as the gold standard method, no evidence of reduced insulin sensitivity in skeletal muscle was documented in RTHβ adult patients; however, higher levels of TC and LDL-C were observed in these patients, which suggest the need for active monitoring of this abnormality to minimize cardiometabolic risk. In addition, we demonstrated, for the first time, that the increase in IL-6 levels in patients with RTHβ is probably secondary to metabolic causes as they have normal levels of TNF-α and CRPus, which may contribute to an increase in cardiovascular risk. A larger number of patients must be studied to confirm these results.

Thyroid hormone receptor-beta agonists in the treatment of metabolically associated steatotic liver disease. Review

Metabolic dysfunction-associated steatotic liver disease, or metabolically-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has become the leading chronic liver disease worldwide in the last decade. The spectrum of MASLD ranges from simple hepatic steatosis to metabolic-associated steatohepatitis (MASH), advanced liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Hepatic inflammation and progressive fibrosis are considered to be the most important driving forces for the progression of MASLD/MASH. Therefore, patients with MASH are a key target group for the development of new therapeutic agents. Although many clinical trials have been conducted in patients with MASLD/MASH over the past two decades, until recently there was no licensed drug for the treatment of this very common metabolic liver disease. Preclinical experimental studies and results from human studies have confirmed the importance of thyroid hormone receptor-β (TGR-β) in the development of hepatic steatosis and stimulated interest in the development of TGR-β agonists as potential treatments for MASLD. The effects of TGR-β agonists, mainly resmetirom, on hepatic and cardiometabolic risk factors have been tested in randomized placebo-controlled trials (RCTs) in patients with MASLD/MASH. As a result of the positive data obtained in the phase III RCT (MAESTRO-NASH), the USA FDA agency on March 14, 2024 accelerated approval of the first TGR-β agonist resmetirom as a drug for the treatment of steatohepatitis associated with metabolic dysfunction. Thus, resmetirom has become the first officially approved drug to be recommended in combination with diet and exercise for use in adults with non-cirrhotic MASH with moderate or advanced liver fibrosis (stages F2-F3 fibrosis).

Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor

ObjectiveThe prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR). MethodsMatrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis. ResultsMatrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD. ConclusionsOur findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.

Canonical and Noncanonical Contribution of Thyroid Hormone Receptor Isoforms Alpha and Beta to Cardiac Hypertrophy and Heart Rate in Male Mice.

Background: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). The aim of this study was to determine invivo which TH receptor (TR)-α or β-and which mode of TR action-canonical gene expression or DNA-binding independent noncanonical action-mediate these effects. Methods: We compared global TRα and TRβ knockout mice (TRαKO; TRβKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRβGS). Hearts were studied with echocardiography at baseline and after 7 weeks of T3 treatment. Gene expression was measured with real-time polymerase chain reaction. Heart rate was recorded with radiotelemetry transmitters for 7 weeks in untreated, hypothyroid, and T3-treated mice. Results: T3 induced ventricular hypertrophy in WT and TRβKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRβ could compensate for absence of TRα. Conclusions: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical but not noncanonical TRα action.