Similar Datasets
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE234233 | GEO
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE234232 | GEO
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE252681 | GEO
Project description:Gluconeogenesis is critical in maintaining blood glucose levels in a normal range during fasting. In this study, we investigated the role of Yin Yang 1 (YY1), a key transcription factor involved in cell proliferation and differentiation, in the regulation of hepatic gluconeogenesis. Our data showed that hepatic YY1 expression levels were induced in mice during fasting conditions and in a state of insulin resistance. Overexpression of YY1 in livers augmented gluconeogenesis, raising fasting blood glucose levels in C57BL/6 mice, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated hyperglycemia in wild-type and diabetic db/db mice. At the molecular level, we further demonstrated that the major mechanism of YY1 in the regulation of hepatic glucose production is to modulate the expression of glucocorticoid receptor. Therefore, our study uncovered for the first time that YY1 participates in the regulation of hepatic gluconeogenesis, which implies that YY1 might serve as a potential therapeutic target for hyperglycemia in diabetes.
| S-EPMC3609554 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is characterized by neurocognitive dysfunctions, such as impaired social interaction and language learning. Gene-environment interactions have a pivotal role in ASD pathogenesis. Nuclear receptor corepressors (NCORs) are transcription co-regulators physically associated with histone deacetylases (HDACs) and many known players in ASD etiology such as transducin ?-like 1 X-linked receptor 1 and methyl-CpG binding protein 2. The epigenome-modifying NCOR complex is sensitive to many ASD risk factors, including HDAC inhibitor valproic acid and a variety of endocrine factors, xenobiotic chemicals, or metabolites that can directly bind to multiple nuclear receptors. Here, we review recent studies of NCORs in neurocognition using animal models and human genetics approaches. We discuss functional interplays between NCORs and other known players in ASD etiology. It is conceivable that the NCOR complex may bridge the in utero environmental risk factors of ASD with epigenetic remodeling and can serve as a converging point for many gene-environment interactions in the pathogenesis of ASD and intellectual disability.
| S-EPMC7842082 | biostudies-literature
Project description:SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a C-terminal SANT (SWI3/ADA2/NCoR/TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.
| S-EPMC1087922 | biostudies-literature
Project description:Histone deacetylase 3 (HDAC3) plays an important role in signal-dependent transcription and is dysregulated in diseases such as cancer. Previous studies have shown that the function of HDAC3 requires an activation step, which is mediated by the interactions of HDAC3 with the deacetylase-activation domain (DAD) of nuclear receptor corepressors and inositol tetraphosphate (IP4). However, the role of the unique HDAC3 C-terminal region in HDAC3 activation is elusive. Here multiple biochemical, structural, and functional studies show that HDAC3 activation requires a priming step mediated by the C terminus to remodel HDAC3 conformation. We show that multiple C-terminal mutations prevent HDAC3 activation by preventing this C terminus-dependent conformational change. Mechanistically, we demonstrate that the C terminus-mediated function in altering HDAC3 conformation is required for proper complex formation of HDAC3 with DAD and IP4 by allowing HDAC3 to undergo IP4-dependent interaction with DAD. Remarkably, we found that this C terminus function is conformation dependent, being necessary for HDAC3 activation prior to but not after the conformational change. Together, our study defines two functional states of free HDAC3, reveals the complete HDAC3 activation pathway, and links the C terminus function to the specific interaction between HDAC3 and DAD. These results also have implications in how signaling pathways may converge on the C terminus to regulate HDAC3 and suggest that the C terminus-mediated conformational change could represent a new target for inhibiting HDAC3 in diseases such as cancer.
| S-EPMC8502911 | biostudies-literature
Project description:Statin therapy is known to increase blood glucose levels in humans. Statins utilize pregnane X receptor (PXR) and serum/glucocorticoid regulated kinase 2 (SGK2) to activate phosphoenolpyruvate carboxykinase 1 (PEPCK1) and glucose-6-phosphatase (G6Pase) genes, thereby increasing glucose production in human liver cells. Here, the novel statin/PXR/SGK2-mediated signaling pathway has now been characterized for hepatic gluconeogenesis. Statin-activated PXR scaffolds the protein phosphatase 2C (PP2C) and SGK2 to stimulate PP2C to dephosphorylate SGK2 at threonine 193. Non-phosphorylated SGK2 co-activates PXR-mediated trans-activation of promoters of gluconeogenic genes in human liver cells, thereby enhancing gluconeogenesis. This gluconeogenic statin-PXR-SGK2 signal is not present in mice, in which statin treatment suppresses hepatic gluconeogenesis. These findings provide the basis for statin-associated side effects such as an increased risk for Type 2 diabetes.
| S-EPMC4585725 | biostudies-literature
Project description:While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, ?-isoform of human GR (hGR?), acts as a dominant-negative inhibitor of the classic hGR? and confers glucocorticoid resistance, the in vivo function of hGR? is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGR? in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGR? significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGR? antagonized GR?'s function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGR? did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGR? regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGR? binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGR?. Finally, our array data demonstrate that hGR? regulates unique components of liver gene expression in vivo by both GR?-dependent and GR?-independent mechanisms.
| S-EPMC4760220 | biostudies-literature
Project description:Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of gluconeogenic enzyme gene expression. Here, we show that SHP inhibited protein kinase A-mediated transcriptional activity of cAMP-response element-binding protein (CREB), a major regulator of glucose metabolism, to modulate hepatic gluconeogenic gene expression. Deletion analysis of phosphoenolpyruvate carboxykinase (PEPCK) promoter demonstrated that SHP inhibited forskolin-mediated induction of PEPCK gene transcription via inhibition of CREB transcriptional activity. In vivo imaging demonstrated that SHP inhibited CREB-regulated transcription coactivator 2 (CRTC2)-mediated cAMP-response element-driven promoter activity. Furthermore, overexpression of SHP using adenovirus SHP decreased CRTC2-dependent elevations in blood glucose levels and PEPCK or glucose-6-phosphatase (G6Pase) expression in mice. SHP and CREB physically interacted and were co-localized in vivo. Importantly, SHP inhibited both wild type CRTC2 and S171A (constitutively active form of CRTC2) coactivator activity and disrupted CRTC2 recruitment on the PEPCK gene promoter. In addition, metformin or overexpression of a constitutively active form of AMPK (Ad-CA-AMPK) inhibited S171A-mediated PEPCK and G6Pase gene expression, and hepatic glucose production and knockdown of SHP partially relieved the metformin- and Ad-CA-AMPK-mediated repression of hepatic gluconeogenic enzyme gene expression in primary rat hepatocytes. In conclusion, our results suggest that a delayed effect of metformin-mediated induction of SHP gene expression inhibits CREB-dependent hepatic gluconeogenesis.
| S-EPMC2952219 | biostudies-literature