Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Hochberg, Irit; Harvey, Innocence; Tran, Quynh; Stephenson, Erin J.; Barkan, Ariel L.; Saltiel, Alan R.; Chandler, William F.; Bridges, Dave

doi:10.1530/endoabs.44.ja1

Cited by 3 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lysosomal-associated transmembrane protein 5 (LAPTM5) [31], involved in lysosome biogenesis and function, has been identified as a potential blood biomarker for hypertensive patients with left ventricular hypertrophy [32] and was upregulated in insulin resistance and obesity [33,34]. Uridine 5′-diphosphate-glucuronosyltransferase 2B4 (UGT2B4), reported linked to metabolism, could convert hydrophobic bile acids into more hydrophilic glucuronide derivatives [35].…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

Xiao

et al. 2022

BMC Med

View full text Add to dashboard Cite

Background Compared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension (aTRH) are at increased risk for cardiovascular and all-cause mortality, independent of blood pressure control. However, the etiopathogenesis of aTRH is still poorly elucidated. Methods We performed a genome-wide association study (GWAS) in first cohort including 586 aTRHs and 871 healthy controls. Next, expression quantitative trait locus (eQTL) analysis was used to identify genes that are regulated by single nucleotide polymorphisms (SNPs) derived from the GWAS. Then, we verified the genes obtained from the eQTL analysis in the validation cohort including 65 aTRHs, 96 hypertensives, and 100 healthy controls through gene expression profiling analysis and real-time quantitative polymerase chain reaction (RT-qPCR) assay. Results The GWAS in first cohort revealed four suggestive loci (1p35, 4q13.2-21.1, 5q22-23.2, and 15q11.1-q12) represented by 23 SNPs. The 23 significant SNPs were in or near LAPTM5, SDC3, UGT2A1, FTMT, and NIPA1. eQTL analysis uncovered 14 SNPs in 1p35 locus all had same regulation directions for SDC3 and LAPTM5. The disease susceptible alleles of SNPs in 1p35 locus were associated with lower gene expression for SDC3 and higher gene expression for LAPTM5. The disease susceptible alleles of SNPs in 4q13.2-21.1 were associated with higher gene expression for UGT2B4. GTEx database did not show any statistically significant eQTLs between the SNPs in 5q22-23.2 and 15q11.1-q12 loci and their influenced genes. Then, gene expression profiling analysis in the validation cohort confirmed lower expression of SDC3 in aTRH but no significant differences on LAPTM5 and UGT2B4, when compared with controls and hypertensives, respectively. RT-qPCR assay further verified the lower expression of SDC3 in aTRH. Conclusions Our study identified a novel association of SDC3 with aTRH, which contributes to the elucidation of its etiopathogenesis and provides a promising therapeutic target.

show abstract

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

Xiao

et al. 2022

BMC Med

View full text Add to dashboard Cite

show abstract

“…Up to 100% of patients with CS show weight excess, mainly associated with visceral obesity. Indeed, GC excess results in increased abdominal visceral adipose tissue deposition and reduced peripheral subcutaneous adipose depots, probably due to the different GC responsiveness of visceral fat compared to subcutaneous fat [6,[19][20][21]. Obesity represents an independent risk factor for development of severe COVID-19 infection, being associated with higher morbidity and mortality [2,22].…”

Section: Obesitymentioning

confidence: 99%

Glucocorticoid excess and COVID-19 disease

Guarnotta

Ferrigno

Martino

et al. 2020

Rev Endocr Metab Disord

View full text Add to dashboard Cite

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing’s syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.

show abstract

“…Por tanto, sería interesante observar si la hipertrofia del ventrículo izquierdo en estos pacientes estaría favorecida por la presencia de algún defecto en la expresión de SRSF4 y GAS5, que hiciera que la actividad del receptor de glucocorticoides estuviera aumentada en los cardiomiocitos. De hecho, los datos del RNA-seq de un estudio que analiza los cambios de expresión génica en tejido adiposo de pacientes con Cushing, muestran que hay una bajada de expresión de SRSF4 y GAS5 en este tejido 55 . Sería interesante observar si esto ocurre también en los cardiomiocitos.…”

Section: Srsf4 En Otros Pacientes Con Hipertrofia Idiopática Y Enfermedad De Cushingunclassified

Caracterización de la función de SRSF4 en la homeostasis del corazón

Alonso¹,

Javier²

View full text Add to dashboard Cite

Rationale: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. Objective: To investigate the role of SRSF3 in cardiac function. Methods and Results: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocytespecific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. Conclusions: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.

show abstract

Gene expression changes in subcutaneous adipose tissue due to Cushing's disease

Cited by 3 publications

References 40 publications

A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

A genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

Glucocorticoid excess and COVID-19 disease

Caracterización de la función de SRSF4 en la homeostasis del corazón

Contact Info

Product

Resources

About