HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes

Non-alcoholic fatty liver disease (NAFLD) is prototypical form of metabolic syndrome and has become a global pandemic. Hepatocytes undergo apoptosis in the pathogenesis of NAFLD. We report that the lymphokine LIGHT/TNFSF14 was upregulated in the murine NAFLD livers and in hepatocytes treated with free fatty acids (palmitate, PA). LIGHT knockdown or neutralization attenuated PA-induced apoptosis of hepatocytes. Similarly, knockdown or blockade of LTβR, the receptor for LIGHT, ameliorated apoptosis in hepatocytes exposed to PA. Ingenuity pathway analysis (IPA) revealed several Notch-related transcription factors as upstream regulators of LIGHT, of which HES5 expression was downregulated paralleling LIGHT induction in the pathogenesis of NAFLD. HES5 knockdown enhanced whereas HES5 over-expression weakened LIGHT induction in hepatocytes. HES5 was found to directly bind to the LIGHT promoter and repress LIGHT transcription. Mechanistically, HES5 interacted with SIRT1 to deacetylate histone H3/H4 on the LIGHT promoter to repress LIGHT transcription. SIRT1 knockdown or inhibition offset the effect of HES5 over-expression on LIGHT transcription and hepatocyte apoptosis. In conclusion, our data unveil a novel mechanism that might contribute to excessive apoptosis in hepatocyte exposed to free fatty acids.

• Publication year

  2021

• Venue

  Cell Death Discovery

• Publication date

  2021-10-23

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41420-021-00707-6PMID 34689159PMCID 8542050
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Yeast Bromodomain Factor 1 and Its Human Homolog TAF1 Play Conserved Roles in Promoting Homologous Recombination

  2021cited by this paper
• Myeloid MKL1 Disseminates Cues to Promote Cardiac Hypertrophy in Mice

  2021cited by this paper
• Myocardin-related transcription factor A (MRTF-A) regulates integrin beta 2 transcription to promote macrophage infiltration and cardiac hypertrophy in mice.

  2021cited by this paper
• BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury

  2021cited by this paper
• Tumor-specific overexpression of histone gene, H3C14 in gastric cancer is mediated through EGFR-FOXC1 axis.

  2021cited by this paper
• The Chromatin Remodeling Protein BRG1 Regulates SREBP Maturation by Activating SCAP Transcription in Hepatocytes

  2021cited by this paper
• Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions

  2021cited by this paper
• BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

  2021cited by this paper
• Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation

  2021cited by this paper
• A KDM4-DBC1-SIRT1 Axis Contributes to TGF-b Induced Mesenchymal Transition of Intestinal Epithelial Cells

  2021cited by this paper
• Choline Kinase Alpha Is a Novel Transcriptional Target of the Brg1 in Hepatocyte: Implication in Liver Regeneration

  2021cited by this paper
• A GSK3-SRF Axis Mediates Angiotensin II Induced Endothelin Transcription in Vascular Endothelial Cells

  2021cited by this paper
• Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production

  2021cited by this paper
• Activation of TC10-Like Transcription by Lysine Demethylase KDM4B in Colorectal Cancer Cells

  2021cited by this paper
• Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation

  2021cited by this paper
• The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells

  2021cited by this paper
• BRG1 Activates PR65A Transcription to Regulate NO Bioavailability in Vascular Endothelial Cells

  2020cited by this paper
• KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism

  2020cited by this paper
• Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial–mesenchymal transition

  2020cited by this paper
• Hepatocyte Notch Signaling Deregulation Related to Lipid Metabolism in Women with Obesity and Nonalcoholic Fatty Liver

  2020cited by this paper
• BRG1 Stimulates Endothelial Derived Alarmin MRP8 to Promote Macrophage Infiltration in an Animal Model of Cardiac Hypertrophy

  2020cited by this paper
• Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid.

  2020cited by this paper
• Activating transcription factor 6 (ATF6) negatively regulates Polo-like kinase 4 expression via recruiting C/EBPβ to the upstream-promoter during ER stress.

  2020cited by this paper
• Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease

  2020cited by this paper
• LncRNA UCA1 Antagonizes Arsenic‐Induced Cell Cycle Arrest through Destabilizing EZH2 and Facilitating NFATc2 Expression

  2020cited by this paper
• An Interplay Between MRTF-A and the Histone Acetyltransferase TIP60 Mediates Hypoxia-Reoxygenation Induced iNOS Transcription in Macrophages

  2020cited by this paper
• An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis

  2020cited by this paper
• NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis

  2020cited by this paper
• Deacetylation of MRTF-A by SIRT1 defies senescence induced down-regulation of collagen type I in fibroblast cells.

  2020cited by this paper
• Nuclear accumulation of MKL1 in luminal breast cancer cells impairs genomic activity of ERα and is associated with endocrine resistance.

  2020cited by this paper
• Smad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production

  2020cited by this paper
• CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels

  2020cited by this paper
• Brahma-Related Gene 1 Deficiency in Endothelial Cells Ameliorates Vascular Inflammatory Responses in Mice

  2020cited by this paper
• USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation

  2020cited by this paper
• ATM‐Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions

  2020cited by this paper
• Identification of genome-wide targets and DNA recognition sequence of the Arabidopsis HMG-box protein AtHMGB15 during cold stress response.

  2020cited by this paper
• Hypoxia regulates allele-specific histone modification of the imprinted H19 gene.

  2020cited by this paper
• Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic

  2020cited by this paper
• Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

  2020cited by this paper
• An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

  2020cited by this paper
• Transcriptional Activation of Matricellular Protein Spondin2 (SPON2) by BRG1 in Vascular Endothelial Cells Promotes Macrophage Chemotaxis

  2020cited by this paper
• Brahma Related Gene 1 (Brg1) Regulates Cellular Cholesterol Synthesis by Acting as a Co-factor for SREBP2

  2020cited by this paper
• Activation of TWIST Transcription by Chromatin Remodeling Protein BRG1 Contributes to Liver Fibrosis in Mice

  2020cited by this paper
• Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

  2020cited by this paper
• From NASH to HCC: current concepts and future challenges

  2019cited by this paper
• Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis

  2019cited by this paper
• PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer

  2019cited by this paper
• NAFLD AND NASH: Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

  2018cited by this paper
• The Role of TNF Family Molecules Light in Cellular Interaction Between Airway Smooth Muscle Cells and T Cells During Chronic Allergic Inflammation

  2018cited by this paper
• Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT.

  2018cited by this paper
• To die or not to die: death signaling in nonalcoholic fatty liver disease

  2018cited by this paper
• Original Ligand for LTβR Is LIGHT: Insight into Evolution of the LT/LTβR System

  2018cited by this paper
• Shining LIGHT on the metabolic role of the cytokine TNFSF14 and the implications on hepatic IL‐6 production

  2018cited by this paper
• Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease.

  2018cited by this paper
• MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1.

  2017cited by this paper
• Transient HES5 Activity Instructs Mesodermal Cells toward a Cardiac Fate

  2017cited by this paper
• FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

  2017cited by this paper
• The effect of palmitate supplementation on gene expression profile in proliferating myoblasts

  2016cited by this paper
• A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice

  2016cited by this paper
• The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.

  2016cited by this paper
• Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation

  2015cited by this paper
• Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model

  2014cited by this paper
• Hey bHLH transcription factors.

  2014cited by this paper
• Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.

  2014cited by this paper
• miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease.

  2013cited by this paper
• Hepatocyte caspase‐8 is an essential modulator of steatohepatitis in rodents

  2013cited by this paper
• NAFLD, NASH and liver cancer

  2013cited by this paper
• Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome

  2011cited by this paper
• LIGHT/TNFSF14 enhances adipose tissue inflammatory responses through its interaction with HVEM

  2011cited by this paper
• Canonical notch pathway protects hepatocytes from ischemia/reperfusion injury in mice by repressing reactive oxygen species production through JAK2/STAT3 signaling

  2011cited by this paper
• Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.

  2010cited by this paper
• Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis.

  2010cited by this paper
• A role for HVEM, but not lymphotoxin‐β receptor, in LIGHT‐induced tumor cell death and chemokine production

  2009cited by this paper
• Apoptosis is associated with CD36/fatty acid translocase upregulation in non‐alcoholic steatohepatitis

  2009cited by this paper
• Dysfunctional very‐low‐density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis

  2009cited by this paper
• DcR3 Protects Islet β Cells from Apoptosis through Modulating Adcyap1 and Bank1 Expression1

  2009cited by this paper
• Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax.

  2008cited by this paper
• Sirt1 protects against high-fat diet-induced metabolic damage

  2008cited by this paper
• Notch signalling: a simple pathway becomes complex

  2006cited by this paper
• Inhibition of Lymphotoxin-β Receptor–Mediated Cell Death by Survivin-ΔEx3

  2006cited by this paper
• Inhibition of lymphotoxin-beta receptor-mediated cell death by survivin-DeltaEx3.

  2006cited by this paper
• Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure.

  2006cited by this paper
• LIGHT sensitizes IFNγ–mediated apoptosis of HT-29 human carcinoma cells through both death receptor and mitochondria pathways

  2004cited by this paper
• Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.

  2003cited by this paper
• LIGHT sensitizes IFNgamma-mediated apoptosis of MDA-MB-231 breast cancer cells leading to down-regulation of anti-apoptosis Bcl-2 family members.

  2003cited by this paper
• LIGHT (a Cellular Ligand for Herpes Virus Entry Mediator and Lymphotoxin Receptor)-Mediated Thymocyte Deletion Is Dependent on the Interaction Between TCR and MHC/Self-Peptide1

  2003cited by this paper
• Mechanisms Regulating Expression of the Tumor Necrosis Factor-related light Gene

  2002cited by this paper
• Hes1 and Hes5 Activities Are Required for the Normal Development of the Hair Cells in the Mammalian Inner Ear

  2001cited by this paper
• Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation

  1999cited by this paper
• LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer.

  1998cited by this paper
• LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator.

  1998cited by this paper

• No citing papers are available for this paper.