Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy

Huang, Jiancheng; Chen, Meng; Hu, Yuxiang; Xia, Weiyi; Zhang, Yihan; Zhao, Chen; Wu, Lianqun

doi:10.3389/fendo.2022.1001349

Cited by 9 publications

(6 citation statements)

References 54 publications

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“…It has been reported that the inflammatory levels significantly upregulated in the adipose tissue and muscle of TAO patients ( Carroll et al, 2013 ; Natesha et al, 1992 ; Khong et al, 2015 ). Huang et al (2022) demonstrated that endoplasmic reticulum stress initiated by cholesterol metabolism may provoke adipose inflammation in TAO. Adipocyte-derived CP and AGT play a critical role in adipogenesis as well as inflammation ( Carroll et al, 2013 ; Bednarek, Wysocki & Sowinski, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy

Wang,

Liu,

Cai

et al. 2023

PeerJ

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Background Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals. Methods RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein–protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT–PCR). Results We identified 183 DEGs in adipose tissue between TAO patients (n = 3) and control patients (n = 3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients (n = 4) are immune and inflammatory response genes compared with the control individual (n = 4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups (P = 0.024). Conclusions Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.

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Section: Discussionmentioning

confidence: 99%

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy

Wang,

Liu,

Cai

et al. 2023

PeerJ

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“…By selecting control samples from the same location as the TED patients, we gained a comparative advantage. Recent literature reports have highlighted the structural, pathophysiological, metabolic, and molecular differences that exist in adipose tissue from different anatomical sites (40,41). In contrast to previous studies on orbital adipose tissue, where control samples were obtained from non-retrobulbar adipose tissue in patients undergoing plastic surgery around the eyes, nose, and ears, which differs from the retrobulbar adipose tissue of TED patients (41), our choice of controls provided a more comparable location.…”

Section: Discussionmentioning

confidence: 99%

“…Recent literature reports have highlighted the structural, pathophysiological, metabolic, and molecular differences that exist in adipose tissue from different anatomical sites (40,41). In contrast to previous studies on orbital adipose tissue, where control samples were obtained from non-retrobulbar adipose tissue in patients undergoing plastic surgery around the eyes, nose, and ears, which differs from the retrobulbar adipose tissue of TED patients (41), our choice of controls provided a more comparable location. For instance, Zhang, et al reported that OATs had higher expression of Iroquois homeobox-family (IRX-3&5) and lower expression in HOX-family/TBX5 compared to white adipose tissue/brown adipose tissue/brown in white adipose tissue development (13).…”

Section: Discussionmentioning

confidence: 99%

Metabolic features of orbital adipose tissue in patients with thyroid eye disease

Wang

Yang

et al. 2023

Front. Endocrinol.

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BackgroundThyroid eye disease (TED) is the most frequent orbital disease in adults and is characterized by the accumulation of orbital adipose tissue (OAT). It can lead to eyelid retraction or even vision loss. Orbital decompression surgery serves as the primary treatment for inactive TED by removing the excess OAT. However, there is a lack of alternative treatments to surgery due to the unclear understanding of the pathogenesis, particularly the metabolic features. Accordingly, our study was implemented to explore the content and features of metabolites of OATs from TED patients.MethodThe OATs used in the current study were obtained from the orbital decompression surgery of seven patients with inactive TED. We also collected control OATs from eye surgical samples of five individuals with no history of autoimmune thyroid diseases, TED, or under non-inflammatory conditions. The liquid chromatography mass spectrometer was used for the measurements of the targeted metabolites. Afterwards, we performed differential metabolite assay analysis and related pathway enrichment analysis.ResultsIn our study, a total of 149 metabolite profiles were detected in all participants. There were significant differences in several metabolite profiles between the TED group and the control group, mainly including uric acid, oxidized glutathione, taurine, dGMP, oxidized glutathione 2, uracil, hexose-phosphate, 1-methylnicotinamide, D-sedoheptulose 1,7-bisphosphate, and uridine 5′-monophosphate (all p-value < 0.05). The TED-related pathways identified included purine metabolism, beta-alanine metabolism, glutathione metabolism (p-values < 0.05). Our study found overlaps and differences including uric acid and uracil, which are in accordance with metabolites found in blood of patients with TED from previous study and several newly discovered metabolite by our study such as hexose-phosphate, 1-methylnicotinamide, D-sedoheptulose 1,7-bisphosphate, compared to those tested from blood, OAT, or urine samples reported in previous studies.ConclusionThe findings of our study shed light on the metabolic features of OAT in individuals with TED. These results may help identify new treatment targets for TED, providing potential avenues for developing alternative treatments beyond ophthalmic surgery.

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“…In orbital tissues from GO patients, Huang et al revealed that ER stress-related gene (ATF6, PERK, and IRE1α) expression was higher than in control orbital tissues [ 51 ]. Further study showed that silencing PERK could reduce oxidative stress and adipogenesis in the GO orbital fibroblasts [ 52 ].…”

Section: Endoplasmic Reticulum (Er) Stress In the Ecm Of Gomentioning

confidence: 99%

The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy

Chiu,

Wu,

Tsai

2024

IJMS

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Graves’ ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves’ disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO.

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Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy

Cited by 9 publications

References 54 publications

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy

Metabolic features of orbital adipose tissue in patients with thyroid eye disease

The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves’ Ophthalmopathy

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