Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells

• Published in: Liver international Vol. 44; no. 1; pp. 125 - 138
• Main Authors: Manka, Paul, Coombes, Jason D., Sydor, Svenja, Swiderska‐Syn, Marzena K., Best, Jan, Gauthier, Karine, Grunsven, Leo A., Oo, Ye H., Wang, Cindy, Diehl, Anna M., Hönes, Georg S., Moeller, Lars C., Figge, Anja, Boosman, René J., Faber, Klaas N., Tannapfel, Andrea, Goetze, Oliver, Aspichueta, Patricia, Lange, Christian M., Canbay, Ali, Syn, Wing‐Kin
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2024
• Subjects: Animals; Cell differentiation; Choline; Diet; Differentiation (biology); Down-regulation; Embryo fibroblasts; Fibroblasts; Fibrosis; Gene expression; Hepatic Stellate Cells - metabolism; Hepatocytes; Hormones; HSC; Humans; Liver; Liver diseases; liver fibrosis; Metabolism; Methionine; Mice; Nutrient deficiency; Phenotypes; Polymerase chain reaction; Receptors; Signal transduction; Stellate cells; TGFβ; Thyroid; Thyroid gland; thyroid hormone receptor α; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Thyroid hormones; Thyroid Hormones - metabolism; Thyroid Hormones - pharmacology; Thyroxine; Transforming Growth Factor beta; Transplantation; Triiodothyronine; Western blotting; Wound healing; TGFβ; HSC; liver fibrosis; thyroid hormone receptor α; thyroid hormones
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.15759

Objective Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis. Design Human liver tissue was obtained from explanted livers following transplantation. TRα‐deficient (TRα‐KO) and wild‐type (WT) mice were fed a control or a profibrogenic methionine‐choline deficient (MCD) diet. Liver tissue was assessed by qRT‐PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor‐specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT‐PCR. Results TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ‐induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα‐KO enhanced MCD diet‐induced liver fibrogenesis. Conclusion These observations indicate that TH action in non‐parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH–TR axis may be a valuable target for future therapy of liver fibrosis.