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: Brittany N Bohinc, Gregory Michelotti, Guanhua Xie, Herbert Pang, Ayako Suzuki, Cynthia D Guy, Dawn Piercy, Leandi Kruger, Marzena Swiderska-Syn, Mariana Machado, Thiago Pereira, Ann Marie Zavacki, Manal Abdelmalek, Anna Mae Diehl
• Journal: Endocrinology (Endocrinology) Vol. 155 Issue 11 Pg. 4591-601 (Nov 2014) ISSN: 1945-7170 [Electronic] United States
• PMID: 25121996 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hedgehog Proteins
• Thyroid Hormones

Topics

• Animals
• Case-Control Studies
• Cells, Cultured
• Gene Expression Regulation
• Hedgehog Proteins (genetics, metabolism)
• Humans
• Hypothyroidism (etiology, metabolism)
• Liver (metabolism, pathology)
• Liver Regeneration (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Non-alcoholic Fatty Liver Disease (genetics, metabolism, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (genetics)
• Stromal Cells (metabolism, pathology)
• Thyroid Hormones (metabolism)
• Wound Healing (physiology)