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Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl4 (1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl4-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl4-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl4-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC14-induced acute liver injury. [ABSTRACT FROM AUTHOR]

Estrogen‐related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)–induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow–derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c‐Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N‐(4‐(diethylaminobenzylidenyl)‐N'‐(4‐hydroxybenzoyl)‐hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA‐mediated knockdown of ERRγ accelerated the formation of bone‐resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL‐stimulated phosphorylation of the nuclear factor κB (NF‐κB) inhibitor IκBα and suppressed NF‐κB transcriptional activity induced by RANKL or the NF‐κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL‐mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss. Our findings identify orphan nuclear receptor ERRγ as a novel negative regulator of osteoclastogenesis and further reveals its protective role on inflammatory bone loss in vivo. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease. [ABSTRACT FROM AUTHOR]

• ERRγ up-regulates LOX gene expression in mouse hepatocytes. • Pro-inflammatory cytokine, IL6 induces LOX gene expression through ERRγ. • The specific inverse agonist of ERRγ inhibits IL6-induced LOX gene expression. Lysyl oxidase (LOX), the copper-dependent extracellular enzyme, plays a critical role in the regulation of protein cross-linking in the extracellular matrix (ECM). It is also involved in liver regeneration and liver fibrosis. However, the mechanism of LOX regulation in mouse hepatocytes is still unclear. Here, we identify a molecular mechanism showing that orphan nuclear receptor estrogen-related receptor γ (ERRγ) regulates LOX gene expression in the presence of the pro-inflammatory cytokine, interleukin 6 (IL6). IL6 significantly stimulated the expression of ERRγ and LOX in mouse hepatocytes. Overexpression of ERRγ increased LOX mRNA and protein levels. Moreover, knockdown of ERRγ attenuated IL6-mediated LOX gene expression at mRNA and protein levels. Overexpression of ERRγ or IL6 treatment upregulated LOX gene promoter activity, while knockdown of ERRγ decreased the IL6-induced LOX promoter activity. Furthermore, GSK5182, a specific ERRγ inverse agonist, inhibited the induction effect of IL6 on LOX promoter activity and gene expression in mouse hepatocytes. Overall, our study elucidates the mechanism involved in the LOX gene regulation by nuclear receptor ERRγ in response to IL6 in mouse hepatocytes, suggesting that, in conditions such as chronic inflammation, IL6 may contribute to liver fibrosis via inducing LOX gene expression. Thus, LOX gene regulation by the inverse agonist of ERRγ can be applied to improve liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor lacking identified natural ligands. The synthetic estrogen receptor ligands 4-hydroxytamoxifen and diethylstilbestrol have, however, been shown to bind to and abolish the constitutive transcriptional activity of ERRγ. Certain phytoestrogens were recently reported to act as agonists of the related ERRα. We investigated whether phytoestrogens also modulated the transcriptional activity of ERRγ. We analyzed a selection of phytoestrogens for their potential agonistic or antagonistic activity on ERRγ. In transiently transfected PC-3 and U2-OS cells equol stimulated the transcriptional activity of ERRγ and enhanced its interaction with the coactivator GRIP1. The agonistic effect of equol was abolished by 4-hydroxytamoxifen. Equol induced a conformational change in the ERRγ ligand-binding domain. Based on structural models of the ERRγ ligand-binding domain, we were able to introduce mutations that modulated the agonistic potential of equol. Finally, equol enhanced the growth inhibitory effect of ERRγ on the prostate cancer PC-3 cells. In conclusion, we have demonstrated that the phytoestrogen equol acts as an ERRγ agonist. [ABSTRACT FROM AUTHOR]

Abstract: Estrogen-related receptors (NR3B family) and Nurr1, NGFI-B, and Nor1 (NR4A family) are orphan nuclear receptors lacking identified natural ligands. The mechanisms regulating their transcriptional activities have remained elusive. We have previously observed that the members of NR3B and NR4A families are coexpressed in certain cell types such as osteoblasts and that the ability of Nurr1 to transactivate the osteopontin promoter is repressed by ERRs. We have now studied the cross-talk between NR3B and NR4A receptors. We show that NR3B and NR4A receptors mutually repress each others’ transcriptional activity. The repression involves intact DNA-binding domains and dimerization interfaces but does not result from competition for DNA binding or from heterodimerization. The activation functions of NR3B and NR4A receptors are dispensable for the cross-talk. In conclusion, we report that cross-talk between NR3B and NR4A receptors is a mechanism modulating the transcriptional activities of these orphan nuclear receptors. [Copyright &y& Elsevier]

Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRγ inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRγ expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRγ expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Pro-inflammatory cytokines dose-dependently increased ERRγ protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRγ overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRγ overexpression in mouse knee joints or ERRγ transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of Esrrg obscured experimental OA. These results indicate that ERRγ is involved in OA pathogenesis. In mouse articular chondrocytes, GSK5182 inhibited pro-inflammatory cytokine-induced catabolic factors. Consistent with the in vitro results, GSK5182 significantly reduced cartilage degeneration in ERRγ-overexpressing mice administered intra-articular Ad-Esrrg. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA. [ABSTRACT FROM AUTHOR]