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The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity

Defective autophagy and lipotoxicity are the hallmarks of nonalcoholic fatty liver disease. However, the precise molecular mechanism for the defective autophagy in lipotoxic conditions is not fully known. In the current study, we elucidated that activation of the mammalian target of rapamycin comple...

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Autores principales: Mushtaq, Arjamand, Ashraf, Nissar Ul, Altaf, Mohammad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9957777/
https://www.ncbi.nlm.nih.gov/pubmed/36690274
http://dx.doi.org/10.1016/j.jbc.2023.102937
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author Mushtaq, Arjamand
Ashraf, Nissar Ul
Altaf, Mohammad
author_facet Mushtaq, Arjamand
Ashraf, Nissar Ul
Altaf, Mohammad
author_sort Mushtaq, Arjamand
collection PubMed
description Defective autophagy and lipotoxicity are the hallmarks of nonalcoholic fatty liver disease. However, the precise molecular mechanism for the defective autophagy in lipotoxic conditions is not fully known. In the current study, we elucidated that activation of the mammalian target of rapamycin complex 1 (mTORC1)–G9a–H3K9me2 axis in fatty acid–induced lipotoxicity blocks autophagy by repressing key autophagy genes. The fatty acid–treated cells show mTORC1 activation, increased histone methyltransferase G9a levels, and suppressed autophagy as indicated by increased accumulation of the key autophagic cargo SQSTM1/p62 and decreased levels of autophagy-related proteins LC3II, Beclin1, and Atg7. Our chromatin immunoprecipitation analysis showed that decrease in autophagy was associated with increased levels of the G9a-mediated repressive H3K9me2 mark and decreased RNA polymerase II occupancy at the promoter regions of Beclin1 and Atg7 in fatty acid–treated cells. Inhibition of mTORC1 in fatty acid–treated cells decreased G9a-mediated H3K9me2 occupancy and increased polymerase II occupancy at Beclin1 and Atg7 promoters. Furthermore, mTORC1 inhibition increased the expression of Beclin1 and Atg7 in fatty acid–treated cells and decreased the accumulation of SQSTM1/p62. Interestingly, the pharmacological inhibition of G9a alone in fatty acid–treated cells decreased the H3K9me2 mark at Atg7 and Beclin1 promoters and restored the expression of Atg7 and Beclin1. Taken together, our findings have identified the mTORC1–G9a–H3K9me2 axis as a negative regulator of the autophagy pathway in hepatocellular lipotoxicity and suggest that the G9a-mediated epigenetic repression is mechanistically a key step during the repression of autophagy in lipotoxic conditions.
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spelling pubmed-99577772023-02-26 The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity Mushtaq, Arjamand Ashraf, Nissar Ul Altaf, Mohammad J Biol Chem Research Article Defective autophagy and lipotoxicity are the hallmarks of nonalcoholic fatty liver disease. However, the precise molecular mechanism for the defective autophagy in lipotoxic conditions is not fully known. In the current study, we elucidated that activation of the mammalian target of rapamycin complex 1 (mTORC1)–G9a–H3K9me2 axis in fatty acid–induced lipotoxicity blocks autophagy by repressing key autophagy genes. The fatty acid–treated cells show mTORC1 activation, increased histone methyltransferase G9a levels, and suppressed autophagy as indicated by increased accumulation of the key autophagic cargo SQSTM1/p62 and decreased levels of autophagy-related proteins LC3II, Beclin1, and Atg7. Our chromatin immunoprecipitation analysis showed that decrease in autophagy was associated with increased levels of the G9a-mediated repressive H3K9me2 mark and decreased RNA polymerase II occupancy at the promoter regions of Beclin1 and Atg7 in fatty acid–treated cells. Inhibition of mTORC1 in fatty acid–treated cells decreased G9a-mediated H3K9me2 occupancy and increased polymerase II occupancy at Beclin1 and Atg7 promoters. Furthermore, mTORC1 inhibition increased the expression of Beclin1 and Atg7 in fatty acid–treated cells and decreased the accumulation of SQSTM1/p62. Interestingly, the pharmacological inhibition of G9a alone in fatty acid–treated cells decreased the H3K9me2 mark at Atg7 and Beclin1 promoters and restored the expression of Atg7 and Beclin1. Taken together, our findings have identified the mTORC1–G9a–H3K9me2 axis as a negative regulator of the autophagy pathway in hepatocellular lipotoxicity and suggest that the G9a-mediated epigenetic repression is mechanistically a key step during the repression of autophagy in lipotoxic conditions. American Society for Biochemistry and Molecular Biology 2023-01-21 /pmc/articles/PMC9957777/ /pubmed/36690274 http://dx.doi.org/10.1016/j.jbc.2023.102937 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Mushtaq, Arjamand
Ashraf, Nissar Ul
Altaf, Mohammad
The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title_full The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title_fullStr The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title_full_unstemmed The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title_short The mTORC1–G9a–H3K9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
title_sort mtorc1–g9a–h3k9me2 axis negatively regulates autophagy in fatty acid–induced hepatocellular lipotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9957777/
https://www.ncbi.nlm.nih.gov/pubmed/36690274
http://dx.doi.org/10.1016/j.jbc.2023.102937
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