As a central metabolic organ, the liver also plays an important role in maintaining glucose homeostasis. The liver produces glucose through glycogenolysis and gluconeogenesis during fasting, while promoting glucose uptake and glycogen storage during feeding.

A key enzyme in the liver, glucokinase (GCK), dictates the direction of hepatic glucose flux, and GCK expression and activity are subject to exquisite regulation. In the postprandial period, the rise in glucose and insulin increases GCK activity, whereas in the fasting state, the combined decrease in glucose and insulin concentrations and increase in glucagon concentrations, decrease GCK activity. The underlying molecular mechanisms regulating GCK expression during feeding cycles are complex at both transcriptional and post-transcriptional levels.

After a meal, insulin upregulates GCK transcription through a PI3K-PKB pathway, and several transcription factors including HNF4a, HIF1a, SREBP1c, and LRH-1 have been implicated in this process. However, much less is known about how GCK expression is downregulated during fasting, and one assumption is that reduced insulin levels during fasting lead to the suppression of GCK transcription.

Among all non-coding RNA species, the most abundant, and possibly also the least understood, is that comprised of long non-coding RNAs (lncRNAs), which are transcripts that are at least 200 nt long and have no coding potential. lncRNAs have been demonstrated to regulate diverse cellular processes ranging from gene transcription, RNA stability, and translation control, but only a small fraction of them have been investigated in a physiologically relevant context.

Researchers 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, authors demonstrate that lncLGR facilitates the recruitment of hnRNPL to the GCK promoter and suppresses GCK transcription.

These data establish a lncRNA-mediated mechanism that regulates hepatic GCK expression and glycogen deposition in a physiological context.

http://www.cell.com/cell-reports/abstract/S2211-1247(16)30040-7