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 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.

Automated summary

The study reveals that METTL3 negatively regulates NASH progression by inhibiting transcription of Cd36 and Ccl2 genes, playing a key role in the transition from NAFL to NASH.