Thyroid Hormone-Related Regulation of Gene Expression in Human Fatty Liver

Pihlajamäki, Jussi; Boes, Tanner; Kim, Eun Young; Dearie, Farrell; Kim, Brian W.; Schroeder, Joshua; Mun, Edward C.; Nasser, Imad; Park, Peter J.; Bianco, Antonio C.; Goldfine, Allison B.; Patti, Mary Elizabeth

doi:10.1210/jc.2009-0212

Cited by 148 publications

(112 citation statements)

References 36 publications

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“…Another possibility is that the RTH action might influence hepatic insulin sensitivity. This hypothesis is supported by a recent report suggesting that T3-responsive genes account for most of the dysregulated transcripts in the livers of obese and insulin resistant subjects (Pihlajamäki et al, 2009).…”

Section: Hypothyroidismsupporting

confidence: 63%

Thyroid hormone action in metabolic regulation

2011

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Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.

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Section: Hypothyroidismsupporting

confidence: 63%

Thyroid hormone action in metabolic regulation

2011

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“…The reason for this effect is not known, but it may result from transcriptional regulation and/or better adaptation to bone marrow niche conditions [15][16][17]. Overall, elevated or normal expression of the components of MRC complex I and II suggests that OXPHOS reaction and electron flow can be properly initiated, but deregulated expression of the members of MRC complex III may "derail" and/or slow down the flow of electrons causing their "leakage".…”

Section: Discussionmentioning

confidence: 99%

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Flis

Irvine

Copland

et al. 2012

Leukemia & Lymphoma

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Mitochondrial respiratory chain (MRC) consists of the protein complexes I, II, III, IV, and V to carry oxidative phosphorylation (OXPHOS), which depends on electron transport to generate ATP. Electron "leakage" from MRC generates reactive oxygen species (ROS). Chronic myeloid leukemia in chronic phase (CML-CP) stem cells (LSCs) produce high levels of mitochondrial ROS causing oxidative DNA damage resulting in genomic instability generating imatinibresistant BCR-ABL1 kinase mutants and additional chromosomal aberrations. Using global mRNA microarray analysis combined with Ingenuity pathway analysis we found that LSCs display enhanced expression of genes encoding MRC complexes I, II, IV, and V. However, expression of genes encoding complex III was deregulated. Treatment with imatinib did not correct the aberrant levels of MRC genes. Therefore we postulate that abnormal expression of MRC genes may facilitate electron "leakage" to promote production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.

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“…TRβ mediates the majority of the actions of T3 in the liver (23), playing an important role in regulating metabolism (24,25), regeneration (26), senescence (27), and carcinogenesis (28). Recent findings suggest that nonalcoholic fatty liver disease, which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma, is associated with impaired thyroid action in the liver (29)(30)(31)(32). We have shown that expression of TRβ1 in liver cancer cells represses TGF-β-mediated proliferation and induction of metalloproteases (33), suggesting that the receptor could antagonize the response to the growth factor and, therefore, influence carcinogenesis.…”

mentioning

confidence: 99%

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Alonso-Merino

Orozco

Ruíz-Llorente

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fund

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Thyroid Hormone-Related Regulation of Gene Expression in Human Fatty Liver

Abstract: These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver.

Cited by 148 publications

References 36 publications

Thyroid hormone action in metabolic regulation

Thyroid hormone action in metabolic regulation

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

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