Estrogen-related Receptor Alpha Research Articles

Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients.

STUDY QUESTIONDo polymorphisms in the anti-Müllerian hormone (AMH) promoter have an effect on AMH levels in patients with polycystic ovary syndrome (PCOS)?SUMMARY ANSWERWe have identified a novel AMH promoter polymorphism rs10406324 that is associated with lower serum AMH levels and is suggested to play a role in the mechanism of regulation of AMH gene expression in women.WHAT IS KNOWN ALREADYFollicle number is positively correlated with serum AMH levels, reflected by elevated AMH levels in women with PCOS. In addition, it is suggested that AMH production per follicle is higher in women with PCOS than in normo-ovulatory women, implying an altered regulation of AMH in PCOS.STUDY DESIGN, SIZE, DURATIONA discovery cohort of 655 PCOS women of Northern European ancestry and both an internal and external validation PCOS cohort (n = 458 and n = 321, respectively) were included in this study. Summary-level data of an AMH genome-wide association study meta-analysis including 7049 normo-ovulatory women was included as a control cohort. A genetic approach was taken through association analysis and in silico analysis of the associated variants in the AMH promoter. In vitro analysis was performed to investigate the functional mechanisms.PARTICIPANTS/MATERIALS, SETTING, METHODSAll common two-allelic single-nucleotide polymorphisms (SNPs) in the region Chr19:2 245 353–2 250 827 bp (Build 37) were selected for the analysis. Linear regression analyses were performed to determine the association between SNPs in the AMH promoter region and serum AMH levels. For the in silico analysis, the webtools ‘HaploReg’ v4.1 for ENCODE prediction weight matrices and ‘atSNP’ were used. In vitro analysis was performed using KK1 cells, a mouse granulosa cell line and COV434 cells, a human granulosa tumor cell line. Cells were transfected with the reference or the variant human AMH promoter reporter construct together with several transcription factors (TFs). Dual-Glo® Luciferase Assay was performed to measure the luciferase activity.MAIN RESULTS AND THE ROLE OF CHANCEPolymorphism rs10406324 was significantly associated with serum AMH levels in all three PCOS cohorts. Carriers of the minor allele G had significantly lower log-transformed serum AMH levels compared to non-carriers (P = 8.58 × 10−8, P = 1.35 × 10−3 and P = 1.24 × 10−3, respectively). This result was validated in a subsequent meta-analysis (P = 3.24 × 10−12). Interestingly, rs10406324 was not associated with follicle count, nor with other clinical traits. Also, in normo-ovulatory women, the minor allele of this variant was associated with lower serum AMH levels (P = 1.04 × 10−5). These findings suggest that polymorphism rs10406324 plays a role in the regulation of AMH expression, irrespective of clinical background. In silico analysis suggested a decreased binding affinity of the TFs steroidogenenic factor 1, estrogen-related receptor alpha and glucocorticoid receptor to the minor allele G variant, however in vitro analysis did not show a difference in promoter activity between the A and G allele.LIMITATIONS, REASONS FOR CAUTIONFunctional analyses were performed in a mouse and a human granulosa cell line using an AMH promoter reporter construct. This may have limited assessment of the impact of the polymorphism on higher order chromatin structures. Human granulosa cells generated from induced pluripotent stem cells, combined with gene editing, may provide a method to elucidate the exact mechanism behind the decrease in serum AMH levels in carriers of the −210 G allele. We acknowledge that the lack of follicle number in the external validation and the control cohort is a limitation of the paper. Although we observed that the association between rs10406324 and AMH levels was independent of follicle number in our discovery and internal validation PCOS cohorts, we cannot fully rule out that the observed effects on serum AMH levels are, in part, caused by differences in follicle number.WIDER IMPLICATIONS OF THE FINDINGSThese results suggest that variations in serum AMH levels are not only caused by differences in follicle number but also by genetic factors. Therefore, the genetic context should be taken into consideration when assessing serum AMH levels in women. This may have clinical consequences when serum AMH levels are used as a marker for the polycystic ovarian morphology phenotype.STUDY FUNDING/COMPETING INTEREST(S)No external funding was used. J.S.E.L. has received consultancy fees from the following companies: Ferring, Roche Diagnostics and Ansh Labs and has received travel reimbursement from Ferring. J.A.V. has received royalties from AMH assays, paid to the institute/lab with no personal financial gain. The other authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A.

LncRNA AGXT2L1-2:2 facilitates keratinocytes proliferation and inhibits apoptosis by interacting with estrogen-related receptor alpha in psoriasis

Our previous studies have revealed that long noncoding RNA (lncRNA) AGXT2L1-2:2 was highly expressed in keratinocytes of psoriasis. However, the functions of lnc-AGXT2L1-2:2 in keratinocytes remain unknown. Meanwhile, co-expression network analysis indicated lnc-AGXT2L1-2:2 could interact with estrogen-related receptor alpha (ERRα). In this study, interleukin (IL)-17A could stimulate the production of lnc-AGXT2L1-2:2 in keratinocytes, thus establishing an in vitro cellular model of psoriasis. Lnc-AGXT2L1-2:2 was overexpressed using lentiviral-vector and ERRα was downregulated with small interfering RNA. Then the effects of lnc-AGXT2L1-2:2 and ERRα on viability, apoptosis, and cell cycle in IL-17A-stimulated keratinocytes were assessed by CCK-8, EdU assay, and flow cytometry. We found that lnc-AGXT2L1-2:2 and ERRα both resulted in higher proliferation ability, lower apoptosis rates, and reduction of G0/G1 phase proportion. Furthermore, lnc-AGXT2L1-2:2 could promote the expression of ERRα and siERRα antagonized the effects of lnc-AGXT2L1-2:2 on the phenotypes above in IL-17A-induced keratinocytes. In conclusion, lnc-AGXT2L1-2:2 was found to promote keratinocytes proliferation, inhibit cell apoptosis and the effects of lnc-AGXT2L1-2:2 on keratinocytes are dependent on ERRα.

Estrogen-related receptor alpha in select host functions and cancer: new frontiers.

Eukaryotic gene expression is under the tight control of transcription factors, which includes the estrogen-related receptor alpha (ERRα). The endogenous ligand(s) acting as ERRα agonist has not been identified and confirmed. ERRα is a prominent member of the nuclear receptors super-family with major roles in energy metabolism, including immunity, cell growth, proliferation and differentiation and a host of other functions in animals. The actions exerted by ERRα towards gene expression regulation are often in association with other transcriptional factors, receptors and signal mediators. Metabolic regulation by ERRα is known for some time that has tremendous impact on host biology like autophagy, angiogenesis, mitochondrial activity, including lipid metabolism. Cellular metabolism and cancer has intricate relationship. On account of the participation of ERRα in metabolism, it has been implicated in various types of cancer onset and progression. In a number of findings, ERRα has been demonstrated to influence several types of cancers, exhibiting as a negative prognostic marker for many. Such diverse role associated with ERRα is due to its interaction with numerous transcriptional factors and other signalling pathways that culminate in providing optimal gene regulation. These observations points to the crucial regulatory roles of ERRα in health and disease. In this article, some of the new findings on the influence of ERRα in host metabolism and biology including cancer, shall be reviewed that will provide a concise understanding of this receptor.

Discovery of JND003 as a New Selective Estrogen-Related Receptor α Agonist Alleviating Nonalcoholic Fatty Liver Disease and Insulin Resistance.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver diseases and is causally linked to hepatic insulin resistance and reduced fatty acid oxidation. Therapeutic treatments targeting both hepatic insulin resistance and lipid oxidative metabolism are considered as feasible strategies to alleviate this disease. Emerging evidence suggests Estrogen-Related Receptor alpha (ERRα), the first orphan nuclear receptor identified, as a master regulator in energy homeostasis by controlling glucose and lipid metabolism. Small molecules improving the functions of ERRα may provide a new option for management of NAFLD. In the present study, by using liver-specific Errα knockout mouse (Errα-LKO), we showed that liver-specific deletion of ERRα exacerbated diet-evoked fatty liver, hepatic and systemic insulin resistance in mice. A potent and selective ERRα agonist JND003 (7) was also discovered. In vitro and in vivo investigation demonstrated that the compound enhanced the transactivation of ERRα downstream target genes, which was accompanied by improved insulin sensitivity and fatty liver symptoms. Furthermore, the therapeutic effects were completely abolished in Errα-LKO mice, indicative of its on-target efficacy. Our study thus suggests that hepatic ERRα is a viable target for NAFLD and that ERRα agonist may serve as an intriguing pharmacological option for management of metabolic diseases.

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Pancreatic cancer (PC) is one of the most fatal and chemoresistant malignancies with a poor prognosis. The current therapeutic options for PC have not achieved satisfactory results due to drug resistance. Therefore, it is urgent to develop novel treatment strategies with enhanced efficacy. This study sought to investigate the anticancer effect of gemcitabine and XCT790, an estrogen-related receptor alpha (ERRα) inverse agonist, as monotherapies or in combination for the treatment of PC. Here we demonstrated that the drug combination synergistically suppressed PC cell viability, its proliferative, migratory, invasive, apoptotic activities, and epithelial-to-mesenchymal transition (EMT), and it triggered G0/G1 cell cycle arrest and programmed cell death in vitro. In addition, in vivo assays using xenograft and mini-PDX (patient-derived xenograft) models further confirmed the synergistic antitumor effect between gemcitabine and XCT790 on PC. Mechanistically, gemcitabine and XCT790 suppressed PC by inhibiting ERRα and MEK/ERK signaling pathway. In conclusion, our current study demonstrated for the first time that gemcitabine combined with XCT790 displayed synergistic anticancer activities against PC, suggesting that their combination might be a promising treatment strategy for the therapy of PC.

Cell-Based Assays to Identify ERR and ERR/PGC Modulators.

The estrogen-related receptor alpha (ERRα, NR3B1) is an orphan nuclear receptor which plays a role in endocrine disruption, energy homeostasis, and cancer prognosis. One of the unique features of this transcription factor is the interplay with its cofactors. For instance, certain modulators require the presence of proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) alongside ERRα. Therefore, identification of ERRα agonists and antagonists require examination of this nuclear receptor alone and together with PGC-1α. In this book chapter, we describe the step-by-step protocol of a multiplex luciferase assay designed to identify ERRα agonists, antagonists, and toxicity in one quantitative high-throughput screening assay using two different stable cell lines.

Errα Promotes Pancreatic Cancer Progression by Enhancing the Transcription of PAI1 and Activating the MEK/ERK Pathway

Introduction: Estrogen-related receptor alpha (ERRα) was reported to be highly associated with the progression and tumorigenesis of several human malignancies. However, the biological role and underlying molecular mechanisms of ERRα in pancreatic cancer (PC) remain unknown.

Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1α/FNDC5/BDNF Pathway.

Methods All rats were randomly divided into four groups, namely, control, CUMS, CUMS + CUR, and CUMS + CUR + SR18292 (PGC-1α inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1α, estrogen-related receptor alpha (ERRα), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1α/FNDC5/BDNF pathway. The PGC-1α inhibitor SR18292 was used to explore the role of PGC-1α in the induction of BDNF by CUR. Results Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. CUR also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of CUR. Conclusion Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.

ERRα expression in ovarian cancer and promotes ovarian cancer cells migration in vitro.

Ovarian cancer is the leading cause of death from a gynaecological malignancy in the developed world, and is characterized by invasion and metastasis and thus causes a high fatality rate. Estrogen-related receptor alpha (ERRα) has been demonstrated to play a widespread and pathophysiological relevant role in tumourigenesis and development. The aim of this study was to investigate the effect of ERRα expression on the progression of ovarian cancer. The correlation between ERRα expression level and clinical pathological parameters in ovarian cancer tissues were analysed via cancer public database CPTAC. The expression level of ERRα in ovarian cancer cells were confirmed by RT-qPCR and Western blot methods. The cellular ERRα expression was up-regulated by lentivirus transfection and down-regulated by specific antagonist. The invasion and metastasis capabilities of ovarian cancer cells were characterized by wound healing assay and trans-well chamber assay. The CPTAC database showed that the ERRα expression levels were higher in the late-stage and high-grade ovarian cancer tissues than in early-stage and low-grade tissues. Ovarian cancer cells with higher-expression ERRα exhibited stronger invasion and metastasis capabilities in vitro. After up-regulating the ERRα expression level, the invasion and metastasis capabilities of ovarian cancer cells were enhanced, while down-regulation weakened. Moreover, the wound sealing rate was positively correlated with the expression of ERRα mRNA expression level (r = 0.921, P < 0.01), and the cell invasiveness was also positively correlated with the cellular ERRα mRNA expression level (r = 0.926, P < 0.01). Our results suggest that ERRα may promote the progression of ovarian cancer, and may serve as a promising predictive biomarker.

PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1.

Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow, which is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status, HMOX1 was required for endothelial alignment to laminar FSS. These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

Relationship Between Myocardial Injury and Expression of PGC-1α and Its Coactivators in Chronic Keshan Disease.

Keshan disease (KD) is a mitochondrial cardiomyopathy. The present study explored the roles of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), the key regulator of mitochondrial structure and function, and its coactivators in myocardial injury in chronic KD. Furthermore, the usefulness of these molecules in the diagnosis of chronic KD was assessed. In the present case-control study, 43 patients with chronic KD and 30 healthy individuals living in KD endemic areas were included. The myocardial injury indicators and mRNA expression levels of PGC-1α, nuclear respiratory factor 1 (NRF1), PPARα, and estrogen-related receptor alpha (ERRα) in peripheral blood were examined. It was found that the levels of atrial natriuretic peptide, creatine kinase, and lactate dehydrogenase (LDH) were higher in patients with chronic KD, when compared to controls, while the level of bradykinin was lower. Furthermore, the PGC-1α, NRF1 and PPARα mRNA levels were higher in patients with KD. The area under the receiver operating characteristic curve and the optimal diagnostic threshold of LDH was 0.937 and 304.0 U/L, respectively. It is noteworthy that the area under the combined receiver operating characteristic curve was larger, when compared to that for LDH detection alone (Z=2.055, P=0.0399). The area under the curve for the "LDH+PPARα" combination was 0.984, with 96.7% sensitivity and 93.0% specificity. The combined detection of LDH and the expression of PPARα can be performed to diagnose the chronic KD.

T-cell Immunometabolism: Therapeutic Implications in Organ Transplantation.

Although solid-organ transplantation has evolved steadily with many breakthroughs in the past 110 y, many problems remain to be addressed, and advanced therapeutic strategies need to be considered. T-cell immunometabolism is a rapidly advancing field that has gathered much attention recently, providing ample mechanistic insight from which many novel therapeutic approaches have been developed. Applications from the field include antitumor and antimicrobial therapies, as well as for reversing graft-versus-host disease and autoimmune diseases. However, the immunometabolism of T cells remains underexplored in solid-organ transplantation. In this review, we will highlight key findings from hallmark studies centered around various metabolic modes preferred by different T-cell subtypes (categorized into naive, effector, regulatory, and memory T cells), including glycolysis, glutaminolysis, oxidative phosphorylation, fatty acid synthesis, and oxidation. This review will discuss the underlying cellular signaling components that affect these processes, including the transcription factors myelocytomatosis oncogene, hypoxia-inducible factor 1-alpha, estrogen-related receptor alpha, and sterol regulatory element-binding proteins, along with the mechanistic target of rapamycin and adenosine monophosphate-activated protein kinase signaling. We will also explore potential therapeutic strategies targeting these pathways, as applied to the potential for tolerance induction in solid-organ transplantation.

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha.(PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells.

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.

Inhibition of mitochondrial pyruvate carrier 1 by lapatinib ditosylate mitigates Alzheimer's-like disease in D-galactose/ovariectomized rats

Mitochondrial, autophagic impairment, excitotoxicity, and also neuroinflammation are implicated in Alzheimer's disease (AD) pathophysiology. We postulated that inhibiting the mitochondrial pyruvate carrier-1 (MPC-1), which inhibits the activation of the mammalian target of rapamycin (mTOR), may ameliorate the neurodegeneration of hippocampal neurons in the rat AD model. To assess this, we used lapatinib ditosylate (LAP), an anti-cancer drug that inhibits MPC-1 through suppression of estrogen-related receptor-alpha (ERR-α), in D-galactose/ovariectomized rats. AD characteristics were developed in ovariectomized (OVX) rats following an 8-week injection of D-galactose (D-gal) (150 mg/kg, i.p.). The human epidermal growth factor receptor-2 (HER-2) inhibitor, LAP (100 mg/kg, p.o.) was daily administered for 3 weeks. LAP protected against D-gal/OVX-induced changes in cortical and hippocampal neurons along with improvement in learning and memory, as affirmed using Morris water maze (MWM) and novel object recognition (NOR) tests. Furthermore, LAP suppressed the hippocampal expression of Aβ1-42, p-tau, HER-2, p-mTOR, GluR-II, TNF-α, P38-MAPK, NOX-1, ERR-α, and MPC-1. Also, LAP treatment leads to activation of the pro-survival PI3K/Akt pathway. As an epilogue, targeting MPC-1 in the D-gal-induced AD in OVX rats resulted in the enhancement of autophagy, and suppression of neuroinflammation and excitotoxicity. Our work proves that alterations in metabolic signaling as a result of inhibiting MPC-1 were anti-inflammatory and neuroprotective in the AD model, revealing that HER-2, MPC-1, and ERR-α may be promising therapeutic targets for AD.

Estrogen protects against acidosis-mediated articular chondrocyte injury by promoting ASIC1a protein degradation

Epidemiological data suggest that the incidence of rheumatoid arthritis (RA) increases in postmenopausal women, which may be related to estrogen deficiency. Tissue acidosis is a common symptom of RA. Acid-sensitive ion channel 1a (ASIC1a), a member of the extracellular H+-activated cation channel family, could be activated by changes in extracellular pH and plays a crucial role in the pathogenesis of RA. As the only cellular component in cartilage tissue, chondrocytes play an extremely important role in maintaining cartilage tissue homeostasis. The aim of this study was to investigate whether estrogen could protect acid-stimulated chondrocytes by regulating the expression of ASIC1a and explore the possible mechanism. The results showed that estrogen could protect against acid-induced chondrocyte injury by reducing ASIC1a protein expression. Moreover, lysosome inhibitor chloroquine (CQ) and autophagy inhibitor 3-methyladeniine (3-MA) could reverse the reduction of ASIC1a protein caused by estrogen, indicating that autophagy-lysosome pathway contributes to estrogen-induced degradation of ASIC1a protein. Furthermore, the down-regulation of ASIC1a expression by estrogen was attenuated by MPP, a specific inhibitor of estrogen-related receptor-alpha (Esrra), indicating that Esrra is involved in the process of estrogen regulating the expression of ASIC1a. Additionally, adenosine 5′-monophosphate (AMP)-activated protein kinase/unc-51-like kinase 1 (AMPK-ULK1) signaling pathway was activated by estrogen treatment, which was abrogated by Esrra-silencing, and AMPK-specific inhibitor Compound C pretreatment could reduce estrogen-induced downregulation of ASIC1a protein. Taken together, these results indicate that estrogen could promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced cytotoxicity, the mechanisms of which might relate to Esrra-AMPK-ULK1 signaling pathway.

Estrogen-related receptor alpha (ERR\u03b1) 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. Here, we report a protective role of ERRα in the intestine. We found that mice deficient in ERRα were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.

Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway.

Simple SummaryThere is increasing evidence that obesity and high circulating cholesterol levels are associated with an increased risk of recurrence and a higher mortality rate in breast cancer patients via altering the metabolic programming in breast cancer cells. However, the underlying molecular mechanism by which high cholesterol levels reprogram the metabolic pathways in breast cancer cells is not well-understood. We have previously demonstrated that cholesterol acts as an endogenous agonist of estrogen-related receptor α (ERRα), a strong regulator of cellular metabolism. The aim of the current study is to demonstrate whether cholesterol/obesity mediates its pathogenic effect in breast cancer cells via altering metabolic pathways in an ERRα-dependent manner. The findings of this study provide mechanistic insights into the link between cholesterol/obesity and metabolic reprogramming in breast cancer patients and reveal the metabolic vulnerabilities in such breast cancer patients that could be therapeutically targeted.The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients.

Estrogen-related receptor α is involved in angiogenesis and skeletal muscle revascularization in hindlimb ischemia.

Skeletal muscle ischemia is a major consequence of peripheral arterial disease (PAD) or critical limb ischemia (CLI). Although therapeutic options for resolving muscle ischemia in PAD/CLI are limited, the issue is compounded by poor understanding of the mechanisms driving muscle vascularization. We found that nuclear receptor estrogen-related receptor alpha (ERRα) expression is induced in murine skeletal muscle by hindlimb ischemia (HLI), and in cultured myotubes by hypoxia, suggesting a potential role for ERRα in ischemic response. To test this, we generated skeletal muscle-specific ERRα transgenic (TG) mice. In these mice, ERRα drives myofiber type switch from glycolytic type IIB to oxidative type IIA/IIX myofibers, which are typically associated with more vascular supply in muscle. Indeed, RNA sequencing and functional enrichment analysis of TG muscle revealed that "paracrine angiogenesis" is the top-ranked transcriptional program activated by ERRα in the skeletal muscle. Immunohistochemistry and angiography showed that ERRα overexpression increases baseline capillarity, arterioles and non-leaky blood vessel formation in the skeletal muscles. Moreover, ERRα overexpression facilitates ischemic neo-angiogenesis and perfusion recovery in hindlimb musculature of mice subjected to HLI. Therefore, ERRα is a hypoxia inducible nuclear receptor that is involved in skeletal muscle angiogenesis and could be potentially targeted for treating PAD/CLI.

Estrogen-related receptor alpha copy number variation is associated with ovarian cancer histological grade.

Copy number variations (CNVs) are related to the genetic and phenotypic diversity of cancers and identifying genetic alterations could improve treatment strategies. Here, we used The Cancer Genome Atlas (TCGA) to explore associations between estrogen-related receptor alpha (ESRRA) CNVs and histological grade in patients with ovarian cancer (OC). Gene expression data and clinical information of 620 OC patients were obtained from The Cancer Genome Atlas）TCGA and associations between ESRRA CNVs and clinical characteristics were evaluated. Multivariate logistic regression analyses to obtain odds ratios (ORs) using a 95% confidence interval (CI) were performed, adjusting for race, age, histological grade, and tumor size. ESRRA CNVs were associated with histological grade (OR 0.6235 [95% CI, 0.3593-0.8877]; p < 0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) CNVs (OR -0.6298 [95% CI, -0.9011 to -0.3585]; p < 0.05). In multivariate analyses, ESRRA CNVs remained significantly associated with histological grade (OR 0.6492 [95% CI, 0.3549-0.9435]; p < 0.05) and PPARGC1A CNVs (OR -0.6236 [95% CI, -0.9269 to 0.3203]; p < 0.05). There was a significant association between ESRRA CNVs in patients with OC and histological grade of the cancer.