The role of N6-methyladenosine methyltransferase RBM15 in non-alcoholic fatty liver disease

Abstract

Abstract Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder with significant health implications. N6-methyladenosine (m6A) methyltransferase is known to exert regulatory functions in liver-related diseases. This study investigates the intricate role of RNA binding motif protein 15 (RBM15) in modulating inflammation and oxidative stress in NAFLD. An NAFLD model was induced in mice (Male, C57BL/6 J, 72 mice in the sham group) through a high-fat diet for 9 weeks, and hepatocytes were exposed to long chain-free fatty acids. The expression levels of RBM15, ring finger protein 5 (RNF5), and rho-kinase 1 (ROCK1) were assessed. RBM15 expression was intervened (injection of AAV9 virus at week 9 and detection at week 11). Liver damage was evaluated using staining assays, along with assessments of weight changes and lipid levels. Notably, RBM15 (decreased about 40%/60%) and RNF5 (decreased about 60%/75%) were poorly expressed while ROCK1 (increased about 2.5-fold) was highly expressed in liver tissues and cells NAFLD. RBM15 overexpression mitigated liver damage, inflammation, and oxidative stress in NAFLD mice, resulting in reduced liver-to-body weight ratio (20%) and decreased levels of alanine aminotransferase (54%), aspartate aminotransferase (36%), total cholesterol (30%), and triglycerides (30%), and inhibited inflammation and oxidative stress level. Mechanistically, RBM15 up-regulated RNF5 expression through m6A methylation modification, and RNF5 suppressed ROCK1 protein levels through ubiquitination modification. RNF5 knockdown or ROCK1 overexpression accelerated inflammation and oxidative stress in NAFLD. Taken together, RBM15 upregulated RNF5 expression through m6A methylation modification. RNF5 inhibited ROCK1 expression through ubiquitination modification to mitigate NAFLD.