The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression
Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogen...
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Published in | Nature communications Vol. 12; no. 1; p. 7213 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
10.12.2021
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of
Mettl3
drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of
Cd36
and
Ccl2
. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic
Mettl3
knockout mice. Hepatic overexpression of
Mettl3
protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the
Cd36
and
Ccl2
genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing
Cd36
and
Ccl2
transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic
Cd36
and
Ccl2
gene transcription
via
a histone modification pathway for protection against NASH progression.
Mechanisms that underlie the progression of non-alcoholic fatty liver disease to the more severe non-alcoholic steatohepatitis are incompletely understood. Here the authors show that METTL3, a RNA methyltransferase that catalyzes mRNA m6 modifications, negatively regulates NASH progression via inhibiting the transcription of
Cd36
and
Ccl2
. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-021-27539-3 |