Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation

Bosscher, Karolien De; Desmet, Sofie; Clarisse, Dorien; Estébanez‐Perpiñá, Eva; Brunsveld, Luc

doi:10.1038/s41574-020-0349-5

Cited by 143 publications

(148 citation statements)

References 159 publications

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“…The effects of estrogens and their receptors on the regulation of liver metabolism and inflammation may be direct or indirect, acting—for example—through other transcription factors and nuclear receptors (NRs) ( 407 ) with relevant and sex-specific activities in the liver ( 408 ) and in the NAFLD pathogenesis ( 409 – 411 ). Such an interplay might be particularly complex and regulated in the female liver: in view of its action in the regulation of reproductive process, ERα might have acquired in the female liver a regulatory role over these signaling pathways to adapt liver metabolism and inflammation to hormonal and nutritional status to accomplish the metabolic adaptations required to support the energy needs of reproduction.…”

Section: Discussionmentioning

confidence: 99%

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

Torre

2020

Front. Endocrinol.

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There is extensive evidence supporting the interplay between metabolism and immune response, that have evolved in close relationship, sharing regulatory molecules and signaling systems, to support biological functions. Nowadays, the disruption of this interaction in the context of obesity and overnutrition underlies the increasing incidence of many inflammatory-based metabolic diseases, even in a sex-specific fashion. During evolution, the interplay between metabolism and reproduction has reached a degree of complexity particularly high in female mammals, likely to ensure reproduction only under favorable conditions. Several factors may account for differences in the incidence and progression of inflammatory-based metabolic diseases between females and males, thus contributing to age-related disease development and difference in life expectancy between the two sexes. Among these factors, estrogens, acting mainly through Estrogen Receptors (ERs), have been reported to regulate several metabolic pathways and inflammatory processes particularly in the liver, the metabolic organ showing the highest degree of sexual dimorphism. This review aims to investigate on the interaction between metabolism and inflammation in the liver, focusing on the relevance of estrogen signaling in counteracting the development and progression of non-alcoholic fatty liver disease (NAFLD), a canonical example of metabolic inflammatory-based liver disease showing a sex-specific prevalence. Understanding the role of estrogens/ERs in the regulation of hepatic metabolism and inflammation may provide the basis for the development of sex-specific therapeutic strategies for the management of such an inflammatory-based metabolic disease and its cardio-metabolic consequences.

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Section: Discussionmentioning

confidence: 99%

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

Torre

2020

Front. Endocrinol.

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“…While permissive heterodimers seem to be lipid sensors that are regulated by many metabolic pathways (PPAR, LXR), non-permissive ones most likely respond to the classical endocrine steroid (ER) and non-steroid (RAR) factors (16). The crosstalk between nuclear receptors through typical (with RXR as a partner) and atypical (with other nuclear receptors) heterodimerization, as well as the alternative splicing of these receptors, poses a challenge to understand nuclear receptors-mediated gene regulation, and explains the variability in drug responses (17,18).…”

Section: The Nuclear Receptorsmentioning

confidence: 99%

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

Alatshan

Benkő

2021

Front. Immunol.

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Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

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“…Indeed, 289 types of nuclear receptors have been reported in Caenorhabditis elegans [ 20 ] and 21 types in Drosophila [ 21 ]. Forty-eight types of nuclear receptors have been found in humans, and 25 of these are orphan receptors with unknown endogenous ligands [ 22 ]. The ligand-dependent action of nuclear receptors includes that the activated receptors translocate into the nucleus, bind to the specific sites of DNA, and regulate the target gene expression to elicit various events, such as cell proliferation, differentiation, reproduction, metabolism, and the maintenance of homeostasis [ 23 , 24 ].…”

Section: Nuclear Receptors As Screening Targetsmentioning

confidence: 99%

Chemical Screening of Nuclear Receptor Modulators

Ishigami‐Yuasa

Kagechika

2020

IJMS

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Nuclear receptors are ligand-inducible transcriptional factors that control multiple biological phenomena, including proliferation, differentiation, reproduction, metabolism, and the maintenance of homeostasis. Members of the nuclear receptor superfamily have marked structural and functional similarities, and their domain functionalities and regulatory mechanisms have been well studied. Various modulators of nuclear receptors, including agonists and antagonists, have been developed as tools for elucidating nuclear receptor functions and also as drug candidates or lead compounds. Many assay systems are currently available to evaluate the modulation of nuclear receptor functions, and are useful as screening tools in the discovery and development of new modulators. In this review, we cover the chemical screening methods for nuclear receptor modulators, focusing on assay methods and chemical libraries for screening. We include some recent examples of the discovery of nuclear receptor modulators.

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Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation

Cited by 143 publications

References 159 publications

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

Chemical Screening of Nuclear Receptor Modulators

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