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1.
J Mol Endocrinol ; 69(2): 329-341, 2022 06 14.
Article in English | MEDLINE | ID: mdl-35521759

ABSTRACT

Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing ß-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining ß-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the nucleosome remodeling and deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrated that Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet ß-cells and established a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1-bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound to the MafA region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet ß-cells under metabolically induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with ß-cell dysfunction associated with T2D.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Homeodomain Proteins/metabolism , Humans , Insulin-Secreting Cells/metabolism , Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics , Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
2.
AACE Clin Case Rep ; 7(4): 273-276, 2021.
Article in English | MEDLINE | ID: mdl-34307852

ABSTRACT

OBJECTIVE: To describe a 4-year-old girl with Graves disease and methimazole allergy who underwent desensitization, allowing continued methimazole use when other treatments were contraindicated. METHODS: We formulated a desensitization plan utilizing cetirizine and prednisone for a patient with previously diagnosed Graves disease who developed urticaria and arthralgias from methimazole. She was admitted for monitoring of rash, urticaria, angioedema, and anaphylaxis. Her methimazole dose was increased as tolerated and then titrated as an outpatient. RESULTS: A 4-year-old girl presented with a heart rate of 195 beats/minute, blood pressure of 145/108, and subsequent labs of undetectable thyroid stimulating hormone (TSH), free T4 5.8 ng/dL, thyroid peroxidase antibody 11.5 IU/ml, and TSH receptor antibody 39.03 IU/L, consistent with Graves disease. She developed urticaria and arthralgias after 2.5 weeks on methimazole, which resolved with drug cessation. Because of her age, the risks of radioactive iodine ablation and surgery were concerning; therefore, methimazole desensitization was attempted. Prednisone (1 mg/kg/day) and cetirizine (5 mg/day) were started prior to low-dose methimazole reintroduction and continued for 7 days. Methimazole was then gradually increased to a final dose of 15 mg daily (0.8 mg/kg/day). Free T4 normalized within a month (1.12 ng/dL), and her TSH normalized within 10 months (4.61 mcU/mL). Except for 2 possible breakthrough allergic responses that resolved with pulse steroids, she continues to tolerate methimazole. CONCLUSION: We describe a case of methimazole desensitization. In this patient, pretreatment with prednisone, coupled with daily cetirizine, successfully induced methimazole tolerance when other treatment modalities were contraindicated.

4.
Mol Pharmacol ; 84(2): 218-26, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23690070

ABSTRACT

Retinoid X receptor α [RXRα; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRα undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXRα function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXRα, yet the contributors, regulators, and consequences of SUMO-RXRα are not well understood. Inflammation and other stressors alter nuclear receptor function in liver and induce SUMOylation of several NRs as part of proinflammatory gene regulation, but linkages between these two pathways in liver, or for RXRα directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXRα in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1ß, and tumor necrosis factor α (TNFα) rapidly and substantially stimulated SUMOylation of RXRα. Two RXRα ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXRα, whereas both inflammation- and ligand-induced SUMOylation of RXRα require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNFα- and 9cRA-stimulated RXRα SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXRα-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXRα, adding to the repertoire of RXRα molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXRα, appears to contribute to the inflammation-induced reduction of RXRα-regulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Inflammation Mediators/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Liver Neoplasms/metabolism , Retinoid X Receptor alpha/metabolism , Sumoylation/drug effects , Alitretinoin , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Interleukin-1beta/metabolism , Ligands , Liver/drug effects , Liver/metabolism , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Organic Chemicals/pharmacology , Protein Processing, Post-Translational/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction/drug effects , Small Ubiquitin-Related Modifier Proteins/metabolism , Tretinoin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
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