Abstract
Glucose levels in mammals are tightly controlled through multiple mechanisms to meet systemic energy demands. Downregulation of hepatic glucokinase (GCK) during fasting facilitates the transition of the liver from a glucose-consuming to a gluconeogenic organ. Here, we report the transcriptional regulation of hepatic GCK by a long non-coding RNA (lncRNA) named liver GCK repressor (lncLGR). lncLGR is induced by fasting, and physiological overexpression of lncLGR to mimic fasting levels effectively suppresses GCK expression and reduces hepatic glycogen content in mice. Consistently, lncLGR knockdown enhances GCK expression and glycogen storage in fasted mice. Mechanistically, lncLGR specifically binds to heterogenous nuclear ribonucleoprotein L (hnRNPL), which is further confirmed to be a transcriptional repressor of GCK in vivo. Finally, we demonstrate that lncLGR facilitates the recruitment of hnRNPL to the GCK promoter and suppresses GCK transcription. Our data establish a lncRNA-mediated mechanism that regulates hepatic GCK expression and glycogen deposition in a physiological context.