scholarly journals Coordinated Recruitment of Histone Methyltransferase G9a and Other Chromatin-Modifying Enzymes in SHP-Mediated Regulation of Hepatic Bile Acid Metabolism

2006 ◽  
Vol 27 (4) ◽  
pp. 1407-1424 ◽  
Author(s):  
Sungsoon Fang ◽  
Ji Miao ◽  
Lingjin Xiang ◽  
Bhaskar Ponugoti ◽  
Eckardt Treuter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Critical Role ◽  
Histone Methyltransferase ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
H3k9 Methylation ◽  
Hepatic Bile

ABSTRACT SHP has been implicated as a pleiotropic regulator of diverse biological functions by its ability to inhibit numerous nuclear receptors. Recently, we reported that SHP inhibits transcription of CYP7A1, a key gene in bile acid biosynthesis, by recruiting histone deacetylases (HDACs) and a Swi/Snf-Brm complex. To further delineate the mechanism of this inhibition, we have examined whether methylation of histones is also involved and whether a functional interplay between chromatin-modifying enzymes occurs. The histone methyltransferase G9a, but not SUV39, was colocalized with SHP in the nucleus and directly interacted with SHP in vitro. G9a, which was coimmunoprecipitated with hepatic SHP, methylated Lys-9 of histone 3 (H3K9) in vitro. Expression of G9a enhanced inhibition of CYP7A1 transcription by SHP, while a catalytically inactive G9a dominant negative (DN) mutant reversed the SHP inhibition. G9a was recruited to and H3K9 was methylated at the CYP7A1 promoter in a SHP-dependent manner in bile acid-treated HepG2 cells. Expression of the G9a-DN mutant inhibited H3K9 methylation, blocked the recruitment of the Brm complex, and partially reversed CYP7A1 inhibition by bile acids. Inhibition of HDAC activity with trichostatin A blocked deacetylation and methylation of H3K9 at the promoter, and, conversely, inhibition of H3K9 methylation by G9a-DN partially blocked deacetylation. Hepatic expression of G9a-DN in mice fed cholic acid disrupted bile acid homeostasis, resulting in increased bile acid pools and partial de-repression of Cyp7a1 and Cyp8b1. Our studies establish a critical role for G9a methyltransferase, histone deacetylases, and the Swi/Snf-Brm complex in the SHP-mediated inhibition of hepatic bile acid synthesis via coordinated chromatin modification at target genes.

scholarly journals Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

2019 ◽  
Author(s):  
Pavan Bhargava ◽  
Leah Mische ◽  
Matthew D. Smith ◽  
Emily Harrington ◽  
Kathryn C Fitzgerald ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
White Matter Lesions ◽  
The Body ◽  
Bile Acid Metabolism ◽  
Dependent Manner ◽  
Microglial Polarization

AbstractMultiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Effects of different digestible carbohydrates on bile acid metabolism and SCFA production by human gut micro-flora grown in an in vitro semi-continuous culture

Anaerobe ◽  
2004 ◽  
Vol 10 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Andrea Zampa ◽  
Stefania Silvi ◽  
Roberto Fabiani ◽  
Guido Morozzi ◽  
Carla Orpianesi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Continuous Culture ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Human Gut

α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

2012 ◽  
Vol 303 (10) ◽  
pp. F1443-F1453 ◽  
Author(s):  
Chung-Hsi Hsing ◽  
Chiou-Feng Lin ◽  
Edmund So ◽  
Ding-Ping Sun ◽  
Tai-Chi Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone H3 ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

scholarly journals Deacetylation of Histone H4 Accompanying Cardiomyogenesis is Weakened in HDAC1-Depleted ES Cells

2018 ◽  
Vol 19 (8) ◽  
pp. 2425 ◽  
Author(s):  
Orazio Angelo Arcidiacono ◽  
Jana Krejčí ◽  
Jana Suchánková ◽  
Eva Bártová
Keyword(s):  
Histone Deacetylases ◽  
Trichostatin A ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cardiomyocyte Differentiation ◽  
Histone H4 ◽  
Epigenetic Factors ◽  
Double Knockout ◽  
Physiological Processes

Cell differentiation into cardiomyocytes requires activation of differentiation-specific genes and epigenetic factors that contribute to these physiological processes. This study is focused on the in vitro differentiation of mouse embryonic stem cells (mESCs) induced into cardiomyocytes. The effects of clinically promising inhibitors of histone deacetylases (HDACi) on mESC cardiomyogenesis and on explanted embryonic hearts were also analyzed. HDAC1 depletion caused early beating of cardiomyocytes compared with those of the wild-type (wt) counterpart. Moreover, the adherence of embryonic bodies (EBs) was reduced in HDAC1 double knockout (dn) mESCs. The most important finding was differentiation-specific H4 deacetylation observed during cardiomyocyte differentiation of wt mESCs, while H4 deacetylation was weakened in HDAC1-depleted cells induced to the cardiac pathway. Analysis of the effect of HDACi showed that Trichostatin A (TSA) is a strong hyperacetylating agent, especially in wt mESCs, but only SAHA reduced the size of the beating areas in EBs that originated from HDAC1 dn mESCs. Additionally, explanted embryonic hearts (e15) responded to treatment with HDACi: all of the tested HDACi (TSA, SAHA, VPA) increased the levels of H3K9ac, H4ac, H4K20ac, and pan-acetylated lysines in embryonic hearts. This observation shows that explanted tissue can be maintained in a hyperacetylation state several hours after excision, which appears to be useful information from the view of transplantation strategy and the maintenance of gene upregulation via acetylation in tissue intended for transplantation.

scholarly journals Role of Stat3 Signaling in Control of EMT of Tubular Epithelial Cells During Renal Fibrosis

2017 ◽  
Vol 42 (6) ◽  
pp. 2552-2558 ◽  
Author(s):  
Jingsong Liu ◽  
Ying Zhong ◽  
Guoyong Liu ◽  
Xiaobai Zhang ◽  
Bofei Xiao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Critical Role ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Phosphorylated Stat3

Background/Aims: Transforming growth factor β 1 (TGFβ1) plays a critical role in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs) during renal injury, a major cause of acute renal failure, renal fibrosis and obstructive nephropathy. However, the underlying molecular mechanisms remain ill-defined. Here, we addressed this question. Methods: Expression of TGFβ1, Snail, and phosphorylated Stat3 was examined by immunohistochemistry in the kidney after induction of unilateral ureteral obstruction (UUO) in mice. In vitro, primary TECs were purified by flow cytometry, and then challenged with TGFβ1 with/without presence of specific inhibitors for phosphorylation of SMAD3 or Stat3. Protein levels were determined by Western blotting. Results: We detected significant increases in Snail and phosphorylated Stat3, an activated form for Stat3, in the kidney after induction of UUO in mice. In vitro, TGFβ1-challenged primary TECs upregulated Snail, in a SMAD3/Stat3 dependent manner. Conclusion: Our study sheds light on the mechanism underlying the EMT of TECs after renal injury, and suggests Stat3 signaling as a promising innovative therapeutic target for prevention of renal fibrosis.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

scholarly journals The Human Candidate Tumor Suppressor Gene HIC1 Recruits CtBP through a Degenerate GLDLSKK Motif

2002 ◽  
Vol 22 (13) ◽  
pp. 4890-4901 ◽  
Author(s):  
Sophie Deltour ◽  
Sébastien Pinte ◽  
Cateline Guerardel ◽  
Bohdan Wasylyk ◽  
Dominique Leprince
Keyword(s):  
Binding Site ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Suppressor Gene ◽  
Close Relative ◽  
Consensus Binding Site ◽  
Candidate Tumor Suppressor Gene

ABSTRACT HIC1 (hypermethylated in cancer) and its close relative HRG22 (HIC1-related gene on chromosome 22) encode transcriptional repressors with five C2H2 zinc fingers and an N-terminal BTB/POZ autonomous transcriptional repression domain that is unable to recruit histone deacetylases (HDACs). Alignment of the HIC1 and HRG22 proteins from various species highlighted a perfectly conserved GLDLSKK/R motif highly related to the consensus CtBP interaction motif (PXDLSXK/R), except for the replacement of the virtually invariant proline by a glycine. HIC1 strongly interacts with mCtBP1 both in vivo and in vitro through this conserved GLDLSKK motif, thus extending the CtBP consensus binding site. The BTB/POZ domain does not interact with mCtBP1, but the dimerization of HIC1 through this domain is required for the interaction with mCtBP1. When tethered to DNA by fusion with the Gal4 DNA-binding domain, the HIC1 central region represses transcription through interactions with CtBP in a trichostatin A-sensitive manner. In conclusion, our results demonstrate that HIC1 mediates transcriptional repression by both HDAC-independent and HDAC-dependent mechanisms and show that CtBP is a HIC1 corepressor that is recruited via a variant binding site.

NF-κB inhibits transcription of the H+-K+-ATPase α2-subunit gene: role of histone deacetylases

2002 ◽  
Vol 283 (5) ◽  
pp. F904-F911 ◽  
Author(s):  
Wenzheng Zhang ◽  
Bruce C. Kone
Keyword(s):  
Histone Deacetylases ◽  
Transcriptional Control ◽  
Protein Complexes ◽  
Trichostatin A ◽  
Collecting Duct ◽  
Proximal Promoter ◽  
Inner Medullary Collecting Duct ◽  
Nuclear Extracts ◽  
Medullary Collecting Duct

The H+-K+-ATPase α2 (HKα2) gene plays a central role in potassium homeostasis, yet little is known about its transcriptional control. We recently demonstrated that the proximal promoter confers basal transcriptional activity in mouse inner medullary collecting duct 3 cells. We sought to determine whether the κB DNA binding element at −104 to −94 influences basal HKα2 gene transcription in these cells. Recombinant NF-κB p50 footprinted the region −116/−94 in vitro. Gel shift and supershift analysis revealed NF-κB p50- and p65-containing DNA-protein complexes in nuclear extracts of mouse inner medullary collecting duct 3 cells. A promoter-luciferase construct with a mutated −104/−94 NF-κB element exhibited higher activity than the wild-type promoter in transfection assays. Overexpression of NF-κB p50, p65, or their combination trans-repressed the HKα2 promoter. The histone deacetylase (HDAC) inhibitor trichostatin A partially reversed NF-κB-mediated trans-repression of the HKα2 promoter. HDAC6 overexpression inhibited HKα2 promoter activity, and HDAC6 coimmunoprecipitated with NF-κB p50 and p65. These results suggest that HDAC6, recruited to the DNA protein complex, acts with NF-κB to suppress HKα2 transcription and identify NF-κB p50 and p65 as novel binding partners for HDAC6.

scholarly journals Atrial Natriuretic Peptide Improves Neurite Outgrowth from Spiral Ganglion Neurons In Vitro through a cGMP-Dependent Manner

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Fei Sun ◽  
Ke Zhou ◽  
Ke-yong Tian ◽  
Jie Wang ◽  
Jian-hua Qiu ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Neurite Outgrowth ◽  
Natriuretic Peptide ◽  
Critical Role ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Dependent Manner ◽  
Ganglion Neurons ◽  
Atrial Natriuretic

The spiral ganglion neurons (SGNs) are the primary afferent neurons in the spiral ganglion (SG), while their degeneration or loss would cause sensorineural hearing loss. As a cardiac-derived hormone, atrial natriuretic peptide (ANP) plays a critical role in cardiovascular homeostasis through binding to its functional receptors (NPR-A and NPR-C). ANP and its receptors are widely expressed in the mammalian nervous system where they could be implicated in the regulation of multiple neural functions. Although previous studies have provided direct evidence for the presence of ANP and its functional receptors in the inner ear, their presence within the cochlear SG and their regulatory roles during auditory neurotransmission and development remain largely unknown. Based on our previous findings, we investigated the expression patterns of ANP and its receptors in the cochlear SG and dissociated SGNs and determined the influence of ANP on neurite outgrowth in vitro by using organotypic SG explants and dissociated SGN cultures from postnatal rats. We have demonstrated that ANP and its receptors are expressed in neurons within the cochlear SG of postnatal rat, while ANP may promote neurite outgrowth of SGNs via the NPR-A/cGMP/PKG pathway in a dose-dependent manner. These results indicate that ANP would play a role in normal neuritogenesis of SGN during cochlear development and represents a potential therapeutic candidate to enhance regeneration and regrowth of SGN neurites.

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