title: Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.
abstract: 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.
authors.affiliation: Divisions of Endocrinology, Diabetes, and Metabolism (B.N.B., D.P.) and Gastroenterology (G.M., G.X., A.S., L.K., M.S.-S., M.M., T.P., M.A., A.M.D.) and Departments of Biostatistics and Bioinformatics (H.P.) and Pathology (C.D.G.), Duke University, Durham, North Carolina 27710; and Division of Endocrinology, Diabetes, and Metabolism (A.M.Z.), Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Bohinc
authors.forename: Gregory
authors.initials: G
authors.lastname: Michelotti
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.forename: Ayako
authors.initials: A
authors.lastname: Suzuki
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Guy
authors.forename: Dawn
authors.initials: D
authors.lastname: Piercy
authors.forename: Leandi
authors.initials: L
authors.lastname: Kruger
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.forename: Mariana
authors.initials: M
authors.lastname: Machado
authors.forename: Thiago
authors.initials: T
authors.lastname: Pereira
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: Manal
authors.initials: M
authors.lastname: Abdelmalek
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000209:etiology* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D013963:Thyroid Hormones