Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte, Lance A.; Wuescher, Leah M.; Marino, Joseph; Hill, Jennifer W.; Eng, Charis; Hinds, Terry D.

doi:10.1074/jbc.m113.544072

Cited by 43 publications

(62 citation statements)

References 49 publications

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“…We previously demonstrated that GR␤ regulates cell growth through an Akt1-PTEN dependent signaling (9). Here we show that hepatic PTEN is suppressed when GR␤ is overexpressed in the liver (Fig.…”

Section: Gr␤ Expression Increases Inmentioning

confidence: 70%

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Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Marino

Stechschulte

Stec

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldGlucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GR␣, as the GR␤ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GR␤ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GR␤ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GR␤ overexpression (GR␤-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GR␤-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-B signaling and increased tumor necrosis factor ␣ (TNF␣) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GR␤-Ad mice had increased glycogen synthase kinase 3␤ (GSK3␤) activity and reduced hepatic PPAR␣ and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the ␤-oxidation pathway. In conclusion, GR␤ antagonizes the GC-induced signaling during fasting via GR␣ and the PPAR␣-FGF21 axis that reduces fat burning. Furthermore, hepatic GR␤ increases inflammation, which leads to hepatic lipid accumulation.

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Section: Gr␤ Expression Increases Inmentioning

confidence: 70%

“…GR␤, however, has a truncated helix 12 and is missing the ligand binding pocket known to bind to GCs (3). The known function of GR␤ is to act as a dominant-negative antagonist to GR␣ (3,5,(7)(8)(9). We have previously shown that GR␤ mRNA increased from fasting and refeeding in the livers of mice (8).…”

mentioning

confidence: 99%

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Marino

Stechschulte

Stec

et al. 2016

Journal of Biological Chemistry

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“…At present, it is not known whether GR␤ specifically inhibits the lipolytic actions of GR␣. But several reports exist showing that GR␤ is regulated metabolically (18,25,62). In cell-based studies, elevated expression of GR␤ mRNA and protein was observed in response to insulin stimulation.…”

Section: Corticosteroid Receptors and Obesitymentioning

confidence: 99%

“…In contrast, GR␤ lacks helix 12 of the ligand-binding domain and does not bind GCs, yet it appears to have intrinsic gene regulatory activity (36). However, most investigations into GR␤ actions suggest that its primary function is to serve as an inhibitor of GR␣ (25,62). Previously, GR␤ expression was thought to be specific to humans.…”

Section: Corticosteroid Receptors and Obesitymentioning

confidence: 99%

The glucocorticoid receptor: cause of or cure for obesity?

John

Marino

Sánchez

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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120

102

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Glucocorticoid hormones (GCs) are important regulators of lipid metabolism, promoting lipolysis with acute treatment but lipogenesis with chronic exposure. Conventional wisdom posits that these disparate outcomes are mediated by the classical glucocorticoid receptor GR␣. There is insufficient knowledge of the GC receptors (GR␣ and GR␤) in metabolic conditions such as obesity and diabetes. We present acute models of GC exposure that induce lipolysis, such as exercise, as well as chronic-excess models that cause obesity and lipid accumulation in the liver, such as hepatic steatosis. Alternative mechanisms are then proposed for the lipogenic actions of GCs, including induction of GC resistance by the GR␤ isoform, and promotion of lipogenesis by GC activation of the mineralocorticoid receptor (MR). Finally, the potential involvement of chaperone proteins in the regulation of adipogenesis is considered. This reevaluation may prove useful to future studies on the steroidal basis of adipogenesis and obesity.

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“…New evidence suggests that hGRβ has an important role in insulin signaling and might be involved in gluconeogenesis and inflammation in mouse liver. 27,28 Furthermore, this isoform was found to participate in the molecular pathways of glioma formation as well as in the migration of bladder cancer cells. [29][30][31] In addition to in vitro and animal experiments, studies in humans have shown that hGRβ expression levels are associated with glucocorticoid resistance in severa l inflammatory diseases (ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, asthma), hematologic malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia) as well as in many mood disorders (major depression, schizophrenia).…”

Section: Glucocorticoid Receptor: From the Nr3c1 Gene To Protein Isofmentioning

confidence: 99%

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

Nicolaides

Charmandari

2017

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Glucocorticoids play a fundamental role in many physiologic functions and contribute substantially to the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated by a ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), which may influence the transcription rate of numerous target genes, interact with other transcription factors, trigger the activation of several kinase pathways or modulate mitochondrial DNA expression. Any genetic defects in the NR3C1 gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologic conditions characterized by partial impaired tissue sensitivity to glucocorticoids. However, there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1 gene. In these cases, several other factors might influence the glucocorticoid signal transduction. In this review, we discuss the numerous glucocorticoid functions and the multiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoid signaling cascade and we summarize the clinical manifestations and pathogenesis of Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculate that the next generation sequencing technologies will undoubtedly enable us to gain a deeper understanding of the GR "interactome".

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Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Cited by 43 publications

References 49 publications

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

The glucocorticoid receptor: cause of or cure for obesity?

Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

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