GR-mediated FTO transactivation induces lipid accumulation in hepatocytes via demethylation of m6A on lipogenic mRNAs

Abstract

ABSTRACT Chronic stress or excessive exposure to glucocorticoids (GC) contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glucocorticoid receptor (GR) mediates the action of GC, but its downstream signalling is not fully understood. Fat mass and obesity associated (FTO) protein and its demethylation substrate N6-methyladenosine (m6A) are both reported to participate in the regulation of lipid metabolism, yet it remains unknown whether they are involved in GC-induced hepatic lipid accumulation as new components of GR signalling. In this study, we use both in vivo and in vitro models of GC-induced hepatic lipid accumulation and demonstrate that the activation of lipogenic genes and accumulation of lipid in liver cells are mediated by GR-dependent FTO transactivation and m6A demethylation on mRNA of lipogenic genes. Targeted mutation of m6A methylation sites and FTO knockdown further validated the role of m6A on 3ʹUTR of sterol regulatory element-binding transcription factor 1 and stearoyl-CoA desaturase mRNAs. Finally, FTO knockdown significantly alleviated dexamethasone-induced fatty liver in mice. These results demonstrate a role of GR-mediated FTO transactivation and m6A demethylation in the pathogenesis of NAFLD and provide new insight into GR signalling in the regulation of fat metablism in the liver.