Writing and erasing ceramides to alter liver disease

Abstract

M⁶A RNA modifications mediate RNA processing and stability. Ceramides are lipid metabolites containing an amino acid-based backbone, which promote metabolic dysfunction. Wang et al. describe a novel m⁶A-dependent regulatory node that tunes ceramide-generating enzymes.

Fig. 1 |. By altering the stability of mRNA transcripts, Mettl3–m⁶A alters sphingolipid metabolism.

Schematic of ceramide synthesis via de novo, salvage and sphingomyelinase pathways (left). Enzyme colour denotes the degree of expression change in Mettl3^ΔHep livers. Visual representation of Mettl3^ΔHep model (right), whereby constitutive liver-specific knockout of Mettl3 reduces methylation of sphingolipid-related mRNA such as Smpd3 mRNA, diminishing transcript decay and leading to an upregulation of ceramide-generating enzymes, ultimately contributing to liver injury.