Nuclear Receptor-Mediated Hepatomegaly and Liver Regeneration: An Update

Zhao, Pengfei; Fan, Shicheng; Gao, Yue; Huang, Min; Bi, Huichang

doi:10.1124/dmd.121.000454

“…The NR superfamily can be divided into three classes based on their ligands and mechanisms of action, including the steroid receptor family, the thyroid/retinoid family, and the orphan receptor family ( Rudraiah et al, 2016 ; Pearen and Muscat, 2012 ; Zheng and Murphy, 2016 ). To date, studies on NRs have elucidated the roles of several NRs in regulating hepatomegaly and liver regeneration, including peroxisome proliferator-activated receptors (PPARα or Nr1c1, and PPARγ or Nr1c3), pregnane X receptor (PXR, Nr1i2), constitutive androstane receptor (CAR, Nr1i3), liver X receptor (LXR, Nr1h3), and farnesoid X receptor (FXR, Nr1h4) ( Zhao et al, 2022 ). Among these genes, Nr1i3 and Nr1h3 also emerged as PHx-repressed Mecp2-activated NRs in our study.…”

Section: Discussionmentioning

confidence: 99%

Mecp2 fine-tunes quiescence exit by targeting nuclear receptors

Yang,

Zou,

Qiu

et al. 2024

eLife

0

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Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit, as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. Genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly, disruption of two nuclear receptors (NRs), Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

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“…The NR superfamily can be divided into three classes based on their ligands and mechanisms of action, including the steroid receptor family, the thyroid/retinoid family and the orphan receptor family 42–44 . To date, studies on NRs have elucidated the roles of several NRs in regulating hepatomegaly and liver regeneration, including peroxisome proliferator-activated receptors (PPARα or Nr1c1, and PPARγ or Nr1c3), pregnane X receptor (PXR, Nr1i2), constitutive androstane receptor (CAR, Nr1i3), liver X receptor (LXR, Nr1h3) and farnesoid X receptor (FXR, Nr1h4) 45 . Among these genes, Nr1i3 and Nr1h3 also emerged as PHx-repressed Mecp2-activated NRs in our study.…”

Section: Discussionmentioning

confidence: 99%

Mecp2 Fine-tunes Quiescence Exit by Targeting Nuclear Receptors

Yang

¹

,

Zou

²

,

Qiu

³

et al. 2023

Preprint

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Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit, as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. Genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly, disruption of two nuclear receptors (NRs), Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

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“…Pregnane X receptor (PXR) (NR1I2) belongs to nuclear receptors superfamily (Zhao et al, 2022). PXR is predominantly expressed in liver and intestine (Moore and Kliewer, 2000;Petryszak et al, 2016;Xing et al, 2020), and plays significant roles in metabolism modulation, cell cycle arrest, inflammation and angiogenesis (Xing et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Exogenous Pregnane X Receptor Does Not Undergo Liquid–Liquid Phase Separation in Nucleus under Cell-Based In Vitro Conditions

Zhao,

Gao,

Zhou

et al. 2024

Drug Metabolism and Disposition

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Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiological and pathological conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biological functions. Till now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation.Analysis of the intrinsically disordered regions (IDRs) using algorithms tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation.Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, CYP3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

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Nuclear Receptor-Mediated Hepatomegaly and Liver Regeneration: An Update

Cited by 16 publications

References 128 publications

Mecp2 fine-tunes quiescence exit by targeting nuclear receptors

Mecp2 fine-tunes quiescence exit by targeting nuclear receptors

Mecp2 Fine-tunes Quiescence Exit by Targeting Nuclear Receptors

Exogenous Pregnane X Receptor Does Not Undergo Liquid–Liquid Phase Separation in Nucleus under Cell-Based In Vitro Conditions

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