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

Abstract

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.

Keywords: Bmal1; METTL3; PPaRα; ROS; YTHDF2; circadian clock; hepatic; lipid metabolism; m(6)A RNA methylation; post-transcriptional regulation.