Abstract
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.
Highlights
Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis
Nonalcoholic fatty liver disease (NAFLD), which ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is one of the most common chronic liver diseases in both developed and developing countries owing to an increased rate of obesity[1,2]
To identify potential regulators that are responsible for the NAFL-to-NASH transition, we assessed two previously published RNA-seq data sets deposited in the Gene Expression Omnibus (GEO) (GEO DataSets: GSE43314 and GSE119340) from WT VS db/db mouse livers and NC VS NASH mouse livers[35,36,37]
Summary
Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. We identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl[3] 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 Ccl[2]. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl[2] gene transcription via a histone modification pathway for protection against NASH progression. 25% of patients with NAFL develop NASH3, which is characterized by hepatic steatosis, liver injury, chronic inflammation, and liver fibrosis and is a key step in the development of cirrhosis and hepatocellular carcinoma (HCC)[3,4]. It is possible that the molecular drivers that coordinate steatosis and inflammation mediate the NAFL-to-NASH transition. METTL14 regulates neurogenesis through the modulation of histone modifications[29]
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