ArticleEndocrinology2014
Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.
Article in Endocrinology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Association between thyroid dysfunction and prognosis in patients with liver failure: a systematic review and meta-analysis.Frontiers in endocrinology · 2025Pooled it
- Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis.Diabetologia · 2026Review
- Pharmacological Potential of Selenoproteins in the Regulation of Oxidative Stress in Liver Diseases.Pharmaceutics · 2026Review
- Article
- Development and validation of a novel analytical method for related substances of resmetirom and identification of new degradation products.Frontiers in chemistry · 2026Article
- Hypothyroidism and the risk of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2026Article
- Interplay between endocrine disorders and liver dysfunction: Mechanisms of damage and therapeutic approaches.World journal of gastroenterology · 2025Review
- Resmetirom in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis.Life (Basel, Switzerland) · 2025Review
- Genome-wide enhancer-gene regulatory maps of liver reveal novel regulatory mechanisms underlying NAFLD pathogenesis.BMC genomics · 2025Article
- Connecting Bone Remodeling and Regeneration: Unraveling Hormones and Signaling Pathways.Biology · 2025Review
- Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH).Nature reviews. Drug discovery · 2025Review
- Resmetirom and thyroid hormone receptor-targeted treatment for metabolic dysfunction-associated steatotic liver disease (MASLD).Portal hypertension & cirrhosis · 2025Article
- Thyroid function and liver fibrosis: FT3 levels are inversely and independently correlated with enhanced liver fibrosis score in solid organ transplant patients with dysglycemia.Frontiers in immunology · 2025Article
- Actions of thyroid hormones and thyromimetics on the liver.Nature reviews. Gastroenterology & hepatology · 2025Review
- Review
- Predictors of controlled attenuation parameter in metabolic dysfunction.United European gastroenterology journal · 2024Article
- Targeting nuclear receptors for NASH/MASH: From bench to bedside.Liver research (Beijing, China) · 2024Article
- Review
- Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression.iScience · 2023Article
- Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.TouchREVIEWS in endocrinology · 2023Review
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
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.
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