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

TitleRepair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism
Authors
KeywordsAnimals
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
Issue Date2014
PublisherThe Endocrine Society. The Journal's web site is located at http://endo.endojournals.org
Citation
Endocrinology, 2014, v. 155 n. 11, p. 4591-4601 How to Cite?
AbstractThyroid 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.
Persistent Identifierhttp://hdl.handle.net/10722/207680
ISSN
2015 Impact Factor: 4.159
2015 SCImago Journal Rankings: 2.363

 

DC FieldValueLanguage
dc.contributor.authorBohinc, BNen_US
dc.contributor.authorMichelotti, Gen_US
dc.contributor.authorXie, Gen_US
dc.contributor.authorPang, HMHen_US
dc.contributor.authorSuzuki, Aen_US
dc.contributor.authorGuy, CDen_US
dc.contributor.authorPiercy, Den_US
dc.contributor.authorKruger, Len_US
dc.contributor.authorSwiderska-Syn, Men_US
dc.contributor.authorMachado, Men_US
dc.contributor.authorPereira, Ten_US
dc.contributor.authorZavacki, AMen_US
dc.contributor.authorAbdelmalek, Men_US
dc.contributor.authorDiehl, AMen_US
dc.date.accessioned2015-01-14T08:33:18Z-
dc.date.available2015-01-14T08:33:18Z-
dc.date.issued2014en_US
dc.identifier.citationEndocrinology, 2014, v. 155 n. 11, p. 4591-4601en_US
dc.identifier.issn0013-7227en_US
dc.identifier.urihttp://hdl.handle.net/10722/207680-
dc.description.abstractThyroid 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.en_US
dc.languageengen_US
dc.publisherThe Endocrine Society. The Journal's web site is located at http://endo.endojournals.orgen_US
dc.relation.ispartofEndocrinologyen_US
dc.subjectAnimalsen_US
dc.subjectCase-Control Studiesen_US
dc.subjectCells, Cultureden_US
dc.subjectGene Expression Regulationen_US
dc.subjectHedgehog Proteins/*genetics/metabolismen_US
dc.subjectHumansen_US
dc.subjectHypothyroidism/*etiology/metabolismen_US
dc.subjectLiver/*metabolism/pathologyen_US
dc.subjectLiver Regeneration/*physiologyen_US
dc.subjectMaleen_US
dc.subjectMiceen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectMice, Transgenicen_US
dc.subjectNon-alcoholic Fatty Liver Disease/genetics/metabolism/physiopathologyen_US
dc.subjectRatsen_US
dc.subjectRats, Sprague-Dawleyen_US
dc.subjectSignal Transduction/geneticsen_US
dc.subjectStromal Cells/*metabolism/pathologyen_US
dc.subjectThyroid Hormones/metabolismen_US
dc.subjectWound Healing/physiologyen_US
dc.titleRepair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidismen_US
dc.typeArticleen_US
dc.identifier.emailPang, HMH: herbpang@hku.hken_US
dc.identifier.authorityPang, HMH=rp01857en_US
dc.identifier.doi10.1210/en.2014-1302en_US
dc.identifier.volume155en_US
dc.identifier.issue11en_US
dc.identifier.spage4591en_US
dc.identifier.epage4601en_US

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