Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

Abstract

Summary: Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether N6-methyladenosine (m6A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m6A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increases m6A mRNA methylation, particularly of PPaRα. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaRα m6A abundance and increases PPaRα mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Mechanistically, YTHDF2 binds to PPaRα to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both in vitro and in vivo increases PPaRα transcript m6A levels, revealing a possible mechanism for circadian disruption on m6A mRNA methylation. These data show that m6A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes. : Zhong et al. reveal that hepatic Bmal1 deletion changes m6A mRNA methylation, particularly of PPaRα. METTL3 or YTHDF2 knockdown affects PPaRα transcription and translation, impacting downstream lipid metabolism. These findings further reveal the overlap between circadian gene network disruption, mRNA m6A modifications, and metabolic state. Keywords: circadian clock, Bmal1, hepatic, lipid metabolism, ROS, m6A RNA methylation, post-transcriptional regulation, METTL3, YTHDF2, PPaRα