Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression

Nuria Lopez-Alcantara; Rebecca Oelkrug; Sarah Christine Sentis; Henriette Kirchner; Jens Mittag

doi:10.1016/j.isci.2023.108064

Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression

Nuria Lopez-Alcantara, Rebecca Oelkrug, Sarah Christine Sentis, Henriette Kirchner, Jens Mittag^*

^*Corresponding author for this work

10 Citations (Scopus)

Abstract

Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists. Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver—rather than isoform—specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.

Original language	English
Article number	108064
Journal	iScience
Volume	26
Issue number	10
Pages (from-to)	108064
ISSN	2589-0042
DOIs	https://doi.org/10.1016/j.isci.2023.108064
Publication status	Published - 20.10.2023

Funding

We thank the Gemeinsame Tierhaltung at the University of Lübeck for excellent animal caretaking. The technical support of Julia Resch from the University of Lübeck and An Ruiter and Marinne Frans from the Endocrine Laboratory Amsterdam UMC is greatly appreciated. We also appreciate the input of Timo Müller from the Helmholtz Munich for the development of the NASH model. The work was funded by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the TRR296 “Local Control of Thyroid Hormone Action” to J.M. (Project-ID 424957847) and in an individual grant to R.O. (Project-ID 434396546). S.C.S. is a student of the DFG funded GRK1957 “Adipocyte-Brain-Crosstalk”. N.L.A. R.O. and S.C.S. conducted experiments; N.L.A. R.O. S.C.S. H.K. and J.M. analyzed the data; H.K. and J.M. supervised and designed the study; N.L.A. and J.M. drafted the manuscript. All authors discussed, corrected, and approved the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. We thank the Gemeinsame Tierhaltung at the University of Lübeck for excellent animal caretaking. The technical support of Julia Resch from the University of Lübeck and An Ruiter and Marinne Frans from the Endocrine Laboratory Amsterdam UMC is greatly appreciated. We also appreciate the input of Timo Müller from the Helmholtz Munich for the development of the NASH model. The work was funded by the Deutsche Forschungsgemeinschaft ( DFG ) in the framework of the TRR296 “ Local Control of Thyroid Hormone Action ” to J.M. (Project-ID 424957847 ) and in an individual grant to R.O. (Project-ID 434396546 ). S.C.S . is a student of the DFG funded GRK1957 “ Adipocyte-Brain-Crosstalk ”.

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2023.108064

Cite this

@article{8839f056831e45ba8ef891e4243ff1e2,

title = "Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression",

abstract = "Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists. Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver—rather than isoform—specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.",

author = "Nuria Lopez-Alcantara and Rebecca Oelkrug and Sentis, \{Sarah Christine\} and Henriette Kirchner and Jens Mittag",

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AU - Sentis, Sarah Christine

AU - Kirchner, Henriette

AU - Mittag, Jens

PY - 2023/10/20

Y1 - 2023/10/20

N2 - Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists. Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver—rather than isoform—specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.

AB - Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists. Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver—rather than isoform—specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.

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Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

CRC/TRR 296 LocoTact: Local control of TH action

Cite this

Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

CRC/TRR 296 LocoTact: Local control of TH action

Cite this