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Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.

Publication ,  Journal Article
Bohinc, BN; Michelotti, G; Xie, G; Pang, H; Suzuki, A; Guy, CD; Piercy, D; Kruger, L; Swiderska-Syn, M; Machado, M; Pereira, T; Zavacki, AM ...
Published in: Endocrinology
November 2014

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.

Duke Scholars

Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

November 2014

Volume

155

Issue

11

Start / End Page

4591 / 4601

Location

United States

Related Subject Headings

  • Wound Healing
  • Thyroid Hormones
  • Stromal Cells
  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Non-alcoholic Fatty Liver Disease
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bohinc, B. N., Michelotti, G., Xie, G., Pang, H., Suzuki, A., Guy, C. D., … Diehl, A. M. (2014). Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology, 155(11), 4591–4601. https://doi.org/10.1210/en.2014-1302
Bohinc, Brittany N., Gregory Michelotti, Guanhua Xie, Herbert Pang, Ayako Suzuki, Cynthia D. Guy, Dawn Piercy, et al. “Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.Endocrinology 155, no. 11 (November 2014): 4591–4601. https://doi.org/10.1210/en.2014-1302.
Bohinc BN, Michelotti G, Xie G, Pang H, Suzuki A, Guy CD, et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. 2014 Nov;155(11):4591–601.
Bohinc, Brittany N., et al. “Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.Endocrinology, vol. 155, no. 11, Nov. 2014, pp. 4591–601. Pubmed, doi:10.1210/en.2014-1302.
Bohinc BN, Michelotti G, Xie G, Pang H, Suzuki A, Guy CD, Piercy D, Kruger L, Swiderska-Syn M, Machado M, Pereira T, Zavacki AM, Abdelmalek M, Diehl AM. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. 2014 Nov;155(11):4591–4601.
Journal cover image

Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

November 2014

Volume

155

Issue

11

Start / End Page

4591 / 4601

Location

United States

Related Subject Headings

  • Wound Healing
  • Thyroid Hormones
  • Stromal Cells
  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Non-alcoholic Fatty Liver Disease
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice