Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

Objective: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH).

Methods: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo.

Results: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH.

Identification of a chromatin-bound ERRα interactome network in mouse liver.

Objectives: Estrogen-related-receptor α (ERRα) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, and perturbations in its activity have been associated with metabolic diseases. While several coactivators and corepressors of ERRα have been identified to date, a knowledge gap remains in understanding the extent to which ERRα cooperates with coregulators in the control of gene expression. Herein, we mapped the primary chromatin-bound ERRα interactome in mouse liver.

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation.

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods and to investigate adaptive hepatic translation during starvation.

Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells.

The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2α becomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis, but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESCs) is largely unexplored.

Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice.

Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH.

Canonical and Nuclear mTOR Specify Distinct Transcriptional Programs in Androgen-Dependent Prostate Cancer Cells.

Unlabelled: mTOR is a serine/threonine kinase that controls prostate cancer cell growth in part by regulating gene programs associated with metabolic and cell proliferation pathways. mTOR-mediated control of gene expression can be achieved via phosphorylation of transcription factors, leading to changes in their cellular localization and activities. mTOR also directly associates with chromatin in complex with transcriptional regulators, including the androgen receptor (AR).

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency.

Objective: Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance.

Methods: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα mutant mice.

Hierarchical Phosphorylation of HOXB13 by mTOR Dictates Its Activity and Oncogenic Function in Prostate Cancer.

Unlabelled: Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and prostate cancer development. Recently, HOXB13 was found to complex with mTOR on chromatin.

ADRA1A-Gα signalling potentiates adipocyte thermogenesis through CKB and TNAP.

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α-adrenergic receptor (AR) and β-AR signalling induces the expression of thermogenic genes of the futile creatine cycle, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo.

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency.

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity.

The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages.

GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that controls messenger RNA translation in response to amino acid availability and ribosome stalling. Here, we show that GCN2 controls erythrocyte clearance and iron recycling during stress. Our data highlight the importance of liver macrophages as the primary cell type mediating these effects.

Chronicle of a discovery: the retinoic acid receptor.

The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid receptors. This stunning breakthrough triggered a cascade of studies to deconstruct the roles played by the RAR and its natural and synthetic ligands in embryonic development, skin, growth, physiology, vision, and disease as well as providing a template to elucidate the molecular mechanisms by which nuclear receptors regulate gene expression. In this review, written from historic and personal perspectives, we highlight the milestones that led to the discovery of the RAR and the subsequent studies that enriched our knowledge of the molecular mechanisms by which a low-abundant dietary compound could be so essential to the generation and maintenance of life itself.

The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1).

La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5'TOP motif, resulting in the displacement of the cap-binding protein eIF4E from TOP mRNAs. However, the involvement of additional signaling pathway in regulating LARP1-mediated inhibition of TOP mRNA translation is largely unexplored.

Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) to identify chromatin-interactome in prostate cancer cells.

Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) is a technique to study protein complexes on chromatin. The protocol below describes specific steps for RIME analysis of the male human-derived prostate cancer cell line LNCaP. This approach can also be applied to other prostate cancer cell lines such as 22Rv1, DU145, and PC3.

Transcriptional control of energy metabolism by nuclear receptors.

Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy.

Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis.

Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response resulting from the dysregulation of a wide range of insulin-controlled cellular processes. However, how insulin affects cellular energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates insulin resistance remains to be elucidated. Herein we reveal that insulin directly enhances the activity of the nuclear receptor ERRα via a GSK3β/FBXW7 signaling axis.

Fatty acid oxidation enzyme Δ3, Δ2-enoyl-CoA isomerase 1 (ECI1) drives aggressive tumor phenotype and predicts poor clinical outcome in prostate cancer patients.

Prostate cancer (PCa) metastases are highly enriched with genomic alterations including a gain at the 16p13.3 locus, recently shown to be associated with disease progression and poor clinical outcome. ECI1, residing at the 16p13.

The mTOR chromatin-bound interactome in prostate cancer.

A growing number of studies support a direct role for nuclear mTOR in gene regulation and chromatin structure. Still, the scarcity of known chromatin-bound mTOR partners limits our understanding of how nuclear mTOR controls transcription. Herein, comprehensive mapping of the mTOR chromatin-bound interactome in both androgen-dependent and -independent cellular models of prostate cancer (PCa) identifies a conserved 67-protein interaction network enriched for chromatin modifiers, transcription factors, and SUMOylation machinery.

Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver.

Estrogen-related receptor alpha (ERRα) is a key regulator of intestinal homeostasis and protects against colitis.

The estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown.

Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer.

Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells.

Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors.

Reactive oxygen species (ROS) such as superoxide anion (O) and hydrogen peroxide (HO) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases.