Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for ...nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the “Big Bang” of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism.
The global epidemic of obesity and its associated chronic diseases is largely attributed to an imbalance between caloric intake and energy expenditure. While physical exercise remains the best ...solution, the development of muscle-targeted “exercise mimetics” may soon provide a pharmaceutical alternative to battle an increasingly sedentary lifestyle. At the same time, these advances are fueling a raging debate on their escalating use as performance-enhancing drugs in high-profile competitions such as the Olympics.
Exercise, especially endurance exercise, is known for its broad health benefits. In this Perspective, Fan et al. summarize exercise-induced transcriptional remodeling in skeletal muscle and present their perspectives of developing natural or synthetic “exercise mimetics” for therapeutic applications in patients that lack adequate physical exercise.
Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can ...lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.
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•Vitamin D receptor (VDR) ligands inhibit hepatic stellate cell activation and fibrosis•Vdr knockout mice spontaneously develop liver fibrosis•TGFβ1 signaling shifts the genome-wide binding locations of VDR•VDR antagonizes SMAD3/TGFβ1 activation of profibrotic genes
In the absence of vitamin D receptor (VDR) signaling, SMADs respond to liver injury by activating a set of genes in hepatic stellate cells that cause fibrosis and liver impairment. Paradoxically, SMAD activity also enables repression of fibrosis by making the chromatin around SMAD target sites more accessible to VDR, which, in the presence of ligands, binds and inhibits SMAD activity.
How the glucocorticoid receptor (GR) activates some genes while potently repressing others remains an open question. There are three current models for suppression: transrepression via GR tethering ...to AP-1/NF-κB sites, direct GR association with inhibitory elements (nGREs), and GR recruitment of the corepressor GRIP1. To gain insights into GR suppression, we used genomic analyses and genome-wide profiling of GR, p65, and c-Jun in LPS-stimulated macrophages. We show that GR mediates both activation and repression at tethered sites, GREs, and GRIP1-bound elements, indicating that motif classification is insufficient to predict regulatory polarity of GR binding. Interestingly, sites of GR repression utilize GRIP1's corepressor function and display reduced histone acetylation. Together, these findings suggest that while GR occupancy confers hormone responsiveness, the receptor itself may not participate in the regulatory effects. Furthermore, transcriptional outcome is not established by sequence but is influenced by epigenetic regulators, context, and other unrecognized regulatory determinants.
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► TLR4 activation dramatically remodels the GR cistrome in macrophages ► Both negative and positive GR enhancers include GREs, NF-κB, and AP-1 sites ► Classical models fail to predict positive or negative polarity of GR regulation ► Hormone treatment marks negative enhancers by histone deacetylation
Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of ...nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of
gei-8, the sole
C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function.
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► Muscle mass and oxidative capacity increase in muscle-specific
NCoR1
−/−
mice ► NCoR1 modulates the activity of transcription factors MEF2, PPARβ/δ, and ERRs ► NCoR1 levels are reduced by physiological conditions that favor fat oxidation ► NCoR1 impact on muscle function is conserved in
C. elegans
Exercise capacity and mitochondrial oxidation are enhanced by the loss of a transcriptional cofactor in muscle cells through modulation of a select set of transcription factors that includes PPARβ/δ.
Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, class IIa ...HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of FOXO family transcription factors. Loss of class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of class IIa HDACs in mouse models of type 2 diabetes ameliorates hyperglycemia, suggesting that inhibitors of class I/II HDACs may be potential therapeutics for metabolic syndrome.
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► Class IIa HDACs play an essential role in activating FOXO via deacetylation ► The fasting hormone glucagon induces class IIa HDAC nuclear translocation in liver ► Class IIa HDACs are inhibited by insulin and metformin-dependent activation of AMPK ► Class IIa HDACs play a critical role in glucose homeostasis and metabolic disease
The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is ...accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA
) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8
T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8
T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA
cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8
T-lymphocyte activation as a tumour-promoting mechanism.
The presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of ...gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis.
Significance Triclosan 5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS is a broad-spectrum antimicrobial agent that has become one of the most common additives used in consumer products. As a result, TCS ...has significantly affected the environment and has been frequently detected in human body fluids. Through a long-term feeding study, we found that TCS enhances hepatocyte proliferation, fibrogenesis, and oxidative stress, which, we believe, can be the driving force for developing advanced liver disease in mice. Indeed, TCS strongly enhances hepatocarcinogenesis after diethylnitrosamine initiation, accelerating hepatocellular carcinoma (HCC) development. Although animal studies require higher chemical concentrations than predicted for human exposure, this study demonstrates that TCS acts as a HCC tumor promoter and that the mechanism of TCS-induced mouse liver pathology may be relevant to humans.
Triclosan 5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.
A hypercaloric diet combined with a sedentary lifestyle is a major risk factor for the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated comorbidities. Standard ...treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive β-cell failure. However, current pharmaceutical options for T2DM are limited in that they do not maintain stable, durable glucose control without the need for treatment intensification. Furthermore, each medication is associated with adverse effects, which range from hypoglycaemia to weight gain or bone loss. Unexpectedly, fibroblast growth factor 1 (FGF1) and its low mitogenic variants have emerged as potentially safe candidates for restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels within hours, without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1 can induce long-lasting remission of the diabetic phenotype. This Review discusses potential mechanisms by which centrally administered FGF1 improves central glucose-sensing and peripheral glucose uptake in a sustained manner. Specifically, we explore the potential crosstalk between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its metabolic actions with FGF15 (rodents), FGF19 (humans) and FGF21.
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