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

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 (m 6 A) 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 m 6 A demethylation on mRNA of lipogenic genes. Targeted mutation of m 6 A methylation sites and FTO knockdown further validated the role of m 6 A 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 m 6 A demethylation in the pathogenesis of NAFLD and provide new insight into GR signalling in the regulation of fat metablism in the liver.

Epitranscriptomics in liver disease: Basic concepts and therapeutic potential

“…90,91 More importantly, FTO knockdown using shRNA significantly alleviated dexamethasone-induced fatty liver in mice. 92 Taken together, these findings suggest that FTO may play a deleterious role in hepatocytes under lipotoxic conditions by altering m 6 A modifications (Fig. 3).…”

“…151 A recent study has demonstrated that MA can prevent oleic acid/dexamethasone-induced increases in total triglycerides in primary hepatocytes. 92 In addition, some natural products targeting RNA methylation have also been reported to have hepatoprotective effects. For instance, the methyl donor betaine can alleviate NAFLD in mice in an FTO-dependent manner, 152 while the yellow polyphenolic pigment curcumin has been shown to attenuate LPS-induced liver injury and liver lipid metabolism disorder by increasing m 6 A RNA methylation 153 ; however, further studies are required to investigate the side effects of these natural products.…”

The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases

“… 107 FTO knockdown significantly mitigates dexamethasone-induced fatty liver (a mouse model of NAFLD). 108 Moreover, it is reported that exenatide therapy ameliorates lipid accumulation and inflammatory changes in NAFLD by decreasing FTO expression in a PI3K-dependent mechanism. 109 …”

Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

“…In the present study, the mechanisms underlying stress resilience-coupled FTO expression in the VTA remains unknown. Considering that dopamine neurons in the VTA are sensitive to stress, which mediates stress susceptibility and resilience, and a recent study ( Hu et al, 2020 ) has reported that glucocorticoid receptor-dependent FTO transactivation induces lipid accumulation in hepatocytes, we hypothesized that a glucocorticoid-regulated FTO expression in the VTA may contribute to stress resilience. Further investigation is required.…”