Mettl3/Mettl14 transactivation and m6A-dependent TGF-β1 translation aggravate non-alcoholic steatohepatitis to fibrosis transition
Description
N6-methyladenosine (m6A) RNA modification has been reported to play an important role in hepatic carcinoma (HCC). Non-alcoholic steatohepatitis (NASH) predisposes the progressive development of liver fibrosis, cirrhosis and HCC, yet whether and how m6A is involved in the critical transition of NASH to fibrosis remains elusive. Here we demonstrate an up-regulation of Mettl3/Mettl14 and global m6A hypermethylation in the liver of high-fat diet-induced NASH and fibrosis rat model, with increased serum lipopolysaccharide (LPS). NF-κB p65 directly transactivates Mettl3/Mettl14, while Mettl3/Mettl14 knockdown prevents profibrotic TGF-β1 secretion from LPS-activated Kupffer cells (KC). Higher m6A level is detected on 5’UTR of TGF-β1 mRNA, which leads to m6A-dependent translation of TGF-β1 mRNA in a cap-independent manner. Our findings identify m6A modification as a new player in p65-mediated inflammatory signaling and TGF-β1-activated fibrosis progression in NASH.