Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma.

Animals Bile Acids and Salts / genetics Carcinoma, Hepatocellular / metabolism Female Glucose / metabolism Hep G2 Cells Homeostasis Humans Liver / pathology Liver Neoplasms / metabolism Male Mice Mice, Inbred C57BL Receptors, Cytoplasmic and Nuclear / metabolism Thymine DNA Glycosylase / metabolism
FXR TET active DNA demethylation bile acids conditional deletion hepatoblastoma hepatocellular carcinoma insulin resistance thymine DNA glycosylase

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
07 04 2020
Historique:
received: 01 09 2019
revised: 14 01 2020
accepted: 12 03 2020
entrez: 9 4 2020
pubmed: 9 4 2020
medline: 28 4 2021
Statut: ppublish

Résumé

Thymine DNA glycosylase (TDG) is a nuclear receptor coactivator that plays an essential role in the maintenance of epigenetic stability in cells. Here, we demonstrate that the conditional deletion of TDG in adult mice results in a male-predominant onset of hepatocellular carcinoma (HCC). TDG loss leads to a prediabetic state, as well as bile acid (BA) accumulation in the liver and serum of male mice. Consistent with these data, TDG deletion led to dysregulation of the farnesoid X receptor (FXR) and small heterodimer partner (SHP) regulatory cascade in the liver. FXR and SHP are tumor suppressors of HCC and play an essential role in BA and glucose homeostasis. These results indicate that TDG functions as a tumor suppressor of HCC by regulating a transcriptional program that protects against the development of glucose intolerance and BA accumulation in the liver.

Identifiants

DOI: 10.1016/j.celrep.2020.03.039 PMID: 32268085
pubmed: 32268085
pii: S2211-1247(20)30353-3
doi: 10.1016/j.celrep.2020.03.039
pii:
doi:

Substances chimiques

Bile Acids and Salts 0
Receptors, Cytoplasmic and Nuclear 0
nuclear receptor subfamily 0, group B, member 2 0
farnesoid X-activated receptor 0C5V0MRU6P
Thymine DNA Glycosylase EC 3.2.2.-
Glucose IY9XDZ35W2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

107475

Subventions

Organisme : CIHR
ID : MOP84423
Pays : Canada
Organisme : CIHR
ID : PJT155982
Pays : Canada
Organisme : CIHR
ID : MOP-106484
Pays : Canada

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Haider M Hassan (HM)

Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.

Majdina Isovic (M)

Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.

Bart Kolendowski (B)

Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.

Natasha Bauer-Maison (N)

Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.

Oladapo Onabote (O)

Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.

Matthew Cecchini (M)

Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.

Aaron Haig (A)

Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.

Saman Maleki Vareki (S)

Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada; Department of Interdisciplinary Medical Sciences, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.

T Michael Underhill (TM)

Department of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.

Joseph Torchia (J)

Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada. Electronic address: jtorchia@uwo.ca.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Acides et sels biliaires › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Cellules HepG2 › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Système digestif › Foie › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Loss of Thymine DNA Glycosylase Causes...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › N-Glycosyl hydrolases › DNA Glycosylases › Thymine DNA glycosylase › Loss of Thymine DNA Glycosylase Causes...