Thyroid Hormone Receptor Sumoylation Is Required for Preadipocyte Differentiation and Proliferation

Ayers, Stephen D.; Milanesi, Anna; Teng, Xiaochun; Rabi, Sina; Akiba, Ysutada; Brent, Gregory A.

doi:10.1074/jbc.m114.600312

Cited by 23 publications

(17 citation statements)

References 71 publications

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“…SLCO4C1 is a member of the transporter superfamily mediating the transport of thyroid hormones,

and

( van der Deure et al 2010 ). It has been shown that when preadipocytes are transduced with an inactive thyroid hormone receptor mutant a decrease in the expression of adipogenic markers is observed ( Liu et al 2015 ). This suggests that increased intracellular thyroid hormone levels, which may be mediated by SLCO4C1, enhance human adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Tung

Peshdary

Gagné

et al. 2017

Environ Health Perspect

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Background:Exposure to flame retardants has been associated with negative health outcomes including metabolic effects. As polybrominated diphenyl ether flame retardants were pulled from commerce, human exposure to new flame retardants such as Firemaster® 550 (FM550) has increased. Although previous studies in murine systems have shown that FM550 and its main components increase adipogenesis, the effects of FM550 in human models have not been elucidated.Objectives:The objectives of this study were to determine if FM550 and its components are active in human preadipocytes, and to further investigate their mode of action.Methods:Human primary preadipocytes were differentiated in the presence of FM550 and its components. Differentiation was assessed by lipid accumulation and expression of peroxisome proliferator-activated receptor normalγ (PPARG), fatty acid binding protein (FABP) 4 and lipoprotein lipase (LPL). mRNA was collected for Poly (A) RNA sequencing and was used to identify differentially expressed genes (DEGs). Functional analysis of DEGs was undertaken in Ingenuity Pathway Analysis.Results:FM550 triphenyl phosphate (TPP) and isopropylated triphenyl phosphates (IPTP), increased adipogenesis in human primary preadipocytes as assessed by lipid accumulation and mRNA expression of regulators of adipogenesis such as PPARγ, CCAAT enhancer binding protein (C/EBP) normalα and sterol regulatory element binding protein (SREBP) 1 as well as the adipogenic markers FABP4 LPL and perilipin. Poly (A) RNA sequencing analysis revealed potential modes of action including liver X receptor/retinoid X receptor (LXR/RXR) activation, thyroid receptor (TR)/RXR, protein kinase A, and nuclear receptor subfamily 1 group H members activation.Conclusions:We found that FM550, and two of its components, induced adipogenesis in human primary preadipocytes. Further, using global gene expression analysis we showed that both TPP and IPTP likely exert their effects through PPARG to induce adipogenesis. In addition, IPTP perturbed signaling pathways that were not affected by TPP. https://doi.org/10.1289/EHP1318

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“…SLCO4C1 is a member of the transporter superfamily mediating the transport of thyroid hormones,

and

Section: Discussionmentioning

confidence: 99%

Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Tung

Peshdary

Gagné

et al. 2017

Environ Health Perspect

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show abstract

“…TRs are expressed and functional in ESC/iPSC and we detected a switch from TRα to TRβ during ESC/iPSC differentiation along the hepatocyte lineage in vitro [ 44 ]. Unliganded TRα is also important in preadipocyte differentiation and myoblast proliferation and differentiation [ 79 , 80 ] and early stages of Xenopus metamorphosis [ 23 , 25 , 26 ]. It will be interesting to ask if these effects also involve actions of predominantly cytoplasmic TRα.…”

Section: Discussionmentioning

confidence: 99%

Ligand Independent and Subtype-Selective Actions of Thyroid Hormone Receptors in Human Adipose Derived Stem Cells

et al. 2016

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Thyroid hormone (TH) receptors (TRs α and β) are homologous ligand-dependent transcription factors (TFs). While the TRs display distinct actions in development, metabolic regulation and other processes, comparisons of TRα and TRβ dependent gene regulation mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, we show that TRα predominates in multipotent human adipose derived stem cells (hADSC) whereas TRβ is expressed at lower levels and is upregulated during hADSC differentiation. The TRs display several unusual properties in parental hADSC. First, TRs display predominantly cytoplasmic intracellular distribution and major TRα variants TRα1 and TRα2 colocalize with mitochondria. Second, knockdown experiments reveal that endogenous TRs influence hADSC cell morphology and expression of hundreds of genes in the absence of hormone, but do not respond to exogenous TH. Third, TRα and TRβ affect hADSC in completely distinct ways; TRα regulates cell cycle associated processes while TRβ may repress aspects of differentiation. TRα splice variant specific knockdown reveals that TRα1 and TRα2 both contribute to TRα-dependent gene expression in a gene specific manner. We propose that TRs work in a non-canonical and hormone independent manner in hADSC and that prominent subtype-specific activities emerge in the context of these unusual actions.

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“…The TR isoforms exist in the nucleus both in the presence and absence of TH and the isoforms have separate ligand-independent and dependent actions that appear to be the result of differential recruitment of co-regulatory protein complexes by the TR. In addition to their basic protein structure the TR isoforms can be modified post-translationally including by sumoylation, which may greatly change their function [9]. …”

Section: The Thyroid Hormone Receptor Isoformsmentioning

confidence: 99%

The actions of thyroid hormone signaling in the nucleus

Vella

Hollenberg

2017

Molecular and Cellular Endocrinology

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Thyroid hormones are a critical regulator of mammalian physiology. Much of their action is due to effects in the nucleus where T3 engages thyroid hormone receptor isoforms to mediate its effects. In order to function properly the TR isoforms must be recruited to regulatory sequences within genes that they up-regulate. On these positive regulated target genes the TR can activate or repress depending upon whether the receptor is bound to T3 or not and the type of co-regulatory proteins present in that cell type. In contrast to T3 mediated activation, the mechanism by which the TR represses transcription in the presence of T3 remains unclear. Herein we will review the components of the transcriptional response to T3 within the nucleus and attempt to highlight the outstanding questions in the field.

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Thyroid Hormone Receptor Sumoylation Is Required for Preadipocyte Differentiation and Proliferation

Cited by 23 publications

References 71 publications

Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Adipogenic Effects and Gene Expression Profiling of Firemaster® 550 Components in Human Primary Preadipocytes

Ligand Independent and Subtype-Selective Actions of Thyroid Hormone Receptors in Human Adipose Derived Stem Cells

The actions of thyroid hormone signaling in the nucleus

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