Repair-Related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism
| Autor: | Anna Mae Diehl, Gregory A. Michelotti, Cynthia D. Guy, Thiago A. Pereira, Mariana Verdelho Machado, Ann Marie Zavacki, Dawn Piercy, Leandi Krüger, Manal F. Abdelmalek, Brittany N. Bohinc, Herbert Pang, Guanhua Xie, Marzena Swiderska-Syn, Ayako Suzuki |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Thyroid Hormones medicine.medical_specialty Stromal cell Cellular differentiation Deiodinase Mice Transgenic Biology Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Hypothyroidism Non-alcoholic Fatty Liver Disease Internal medicine medicine Animals Humans Hedgehog Proteins Thyroid-TRH-TSH Cells Cultured 030304 developmental biology Regulation of gene expression Wound Healing 0303 health sciences Liver regeneration Hedgehog signaling pathway Liver Regeneration Rats Mice Inbred C57BL medicine.anatomical_structure Gene Expression Regulation Liver Case-Control Studies Hepatocyte biology.protein 030211 gastroenterology & hepatology Stromal Cells Signal Transduction Hormone |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (T4) is converted into active hormone (T3) by deiodinase 1 (D1) but into inactive hormone (rT3) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, whereas stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repair-related changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum rT3. Moreover, the decreases in the free T3 to rT3 and free T4 to rT3 ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T4. In conclusion, the Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for cellular differentiation. |
| Databáze: | OpenAIRE |
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