In Vitro Investigation of HIF-1α as a Therapeutic Target for Thyroid-Associated Ophthalmopathy

• Published in: Endocrinology and metabolism (Seoul) Vol. 39; no. 5; pp. 767 - 776
• Main Authors: Lee, Jeongmin, Lee, Jinsoo, Baek, Hansang, Lim, Dong-Jun, Lee, Seong-Beom, Lee, Jung-Min, Jang, Sang-Ah, Kang, Moo Il, Yang, Suk-Woo, Kim, Min-Hee
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Endocrine Society 01.10.2024; 대한내분비학회
• Subjects: Adipogenesis; Adult; Cell Differentiation; Cell Hypoxia; Cells, Cultured; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; graves ophthalmopathy; Graves Ophthalmopathy - drug therapy; Graves Ophthalmopathy - metabolism; Graves Ophthalmopathy - pathology; Humans; hypoxia; hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Middle Aged; Orbit - metabolism; Orbit - pathology; Original; PPAR gamma - metabolism; thyroid; 내과학; Hypoxia; Hypoxia-inducible factor 1; Graves ophthalmopathy; Adipogenesis; Thyroid
• ISSN: 2093-596X; 2093-5978; 2093-5978
• DOI: 10.3803/EnM.2024.1952

Background: Thyroid-associated ophthalmopathy (TAO) involves tissue expansion and inflammation, potentially causing a hypoxic microenvironment. Hypoxia-inducible factor (HIF)-1α is crucial in fibrosis and adipogenesis, which are observed in TAO progression. We investigated the effects of hypoxia on orbital fibroblasts (OFs) in TAO, focusing on the role of HIF-1α in TAO progression.Methods: OFs were isolated from TAO and non-TAO patients (as controls). In addition to HIF-1α, adipogenic differentiation markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (CEBP) were measured by Western blot, and phenotype changes were evaluated by Oil Red O staining under both normoxia and hypoxia. To elucidate the effect of HIF-1α inhibition, protein expression changes after HIF-1α inhibitor treatment were evaluated under normoxia and hypoxia.Results: TAO OFs exhibited significantly higher HIF-1α expression than non-TAO OFs, and the difference was more distinct under hypoxia than under normoxia. Oil Red O staining showed that adipogenic differentiation of TAO OFs was prominent under hypoxia. Hypoxic conditions increased the expression of adipogenic markers, namely PPARγ and CEBP, as well as HIF-1α in TAO OFs. Interleukin 6 levels also increased in response to hypoxia. The effect of hypoxia on adipogenesis was reduced at the protein level after HIF-1α inhibitor treatment, and this inhibitory effect was sustained even with IGF-1 stimulation in addition to hypoxia.Conclusion: Hypoxia induces tissue remodeling in TAO by stimulating adipogenesis through HIF-1α activation. These data could provide insights into new treatment strategies and the mechanisms of adipose tissue remodeling in TAO.