Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Mamrosh, Jennifer L.; Lee, Jae Man; Wagner, Martin; Stambrook, Peter J.; Whitby, Richard J.; Sifers, Richard N.; Wu, San‐Pin; Tsai, Ming‐Jer; DeMayo, Francesco J.; Moore, David D.

doi:10.7554/elife.01694

Cited by 64 publications

(71 citation statements)

References 47 publications

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“…More importantly, NR5A2 has been proposed as a key element in a novel pathway for endoplasmic reticulum stress resolution in the liver [35]. In this pathway, NR5A2 is proposed to activate polo-like kinase 3 (PLK3), which phosphorylates Activating Transcription Factor 2 (ATF2).…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

Arvaniti

Vakrakou

Kaltezioti

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Section: Discussionmentioning

confidence: 99%

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

Arvaniti

Vakrakou

Kaltezioti

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…It is also required for hepatic endoplasmic reticulum (ER) stress resolution through transcriptional control of polo-like kinase 3 (Plk3) and subsequent phosphorylation of activating transcription factor 2 (ATF2) (Mamrosh et al 2014). To understand the robust tumor-suppressive phenotype, we first assessed the β-catenin pathway in mid-term DEN-treated livers in which tumors…”

Section: Hepatic Loss Of Lrh-1 Prevents Den-induced Liver Carcinogenesismentioning

confidence: 99%

LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer

Oosterveer

Stein

et al. 2016

Genes Dev.

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Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamineinduced metabolism and signaling to promote hepatocellular carcinogenesis.Supplemental material is available for this article.Received January 7, 2016; revised version accepted May 12, 2016.During tumorigenesis, cancer cells usually switch from oxidative metabolism to a highly glycolytic metabolic status (Vander Heiden et al. 2009). While glucose is predominantly metabolized into lactate rather than entering the tricarboxylic acid (TCA) cycle, cancer cells particularly rely on glutamine to replenish TCA cycle intermediates. This process, termed anaplerosis, is accomplished through the conversion of glutamine to α-ketoglutarate (α-KG) via a two-step deamination reaction catalyzed by glutaminases and then by glutamate dehydrogenase 1 (GLUD1) or transaminases Wise et al. 2008;Csibi et al. 2013;Son et al. 2013). Cancer cells therefore critically depend on glutamine as a fuel for proliferation, and abrogation of glutamine metabolism blocks tumorigenesis, indicating an accessible therapeutic window for cancer treatment (Hensley et al. 2013).Liver receptor homolog 1 (LRH-1; also called NR5A2) is a nuclear receptor that is enriched in enterohepatic tissues, where it has diverse molecular and physiological functions (Stein and Schoonjans 2015). LRH-1 has been linked to cell proliferation and cancer development in the intestine (Botrugno et al. 2004;Schoonjans et al. 2005) and pancreas (Petersen et al. 2010;Benod et al. 2011). In the liver, LRH-1 regulates various metabolic processes, including bile acid synthesis (Mataki et al. 2007;Lee et al. 2008;Out et al. 2011), glucose sensing and processing (Oosterveer et al. 2012), and reverse cholesterol transport (Stein et al. 2014). Although the function of LRH-1 in the liver has been extensively studied, its commanding role in intermediary metabolism has never been connected to tumorigenesis.In this study, we report that LRH-1 promotes diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) by coordinating glutamine-induced anabolic metabo...

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“…New evidence suggests that LRH-1 may also be targeted to relieve chronic endoplasmic reticulum stress. Activation of LRH-1 by synthetic DLPC or the small molecule RJW100 induces Plk3, which is required for the activation of ATF2 and the induction of its target genes, which play a key role in resolving ER stress (15). Given its potential therapeutic value, LRH-1 has been the subject of multiple attempts to identify small molecule modulators (16 -19).…”

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confidence: 99%

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

Musille

Kossmann

Kohn

et al. 2016

Journal of Biological Chemistry

103

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Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine, favors LRH-1's interaction with transcriptional coactivators to up-regulate gene expression. Both crystallographic and solution-based structural studies showed that dilauroylphosphatidylcholine binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the ␤-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences co-regulator selectivity remains elusive. Here, we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 is correlated with the strength of the co-regulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.

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Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Cited by 64 publications

References 47 publications

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

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