p53 promotes the expression of gluconeogenesis-related genes and enhances hepatic glucose production

In an attempt to comprehensively define metabolic pathways regulated by p53, we performed two consecutive high-throughput analyses in human liver-derived cells with varying p53 statuses. A gene expression microarray screen followed by constraint-based modeling (CBM) predicting metabolic changes imposed by the transcriptomic changes suggested a role for p53 in enhancing gluconeogenesis (de novo synthesis of glucose). Examining glucogenic gene expression revealed a p53-dependent induction of genes involved in both gluconeogenesis (G6PC, PCK2) and in supplying glucogenic precursors (glycerol kinase (GK), aquaporin 3 (AQP3), aquaporin 9 (AQP9) and glutamic-oxaloacetic transaminase 1 (GOT1)). Accordingly, p53 augmented hepatic glucose production (HGP) in both human liver cells and primary mouse hepatocytes.These findings portray p53 as a novel regulator of glucose production. By facilitating glucose export, p53 may prevent it from being shunted to pro-cancerous pathways such as glycolysis and the PPP. Thus, our findings suggest a metabolic pathway through which p53 may inhibit tumorigenesis.p53 is a transcription factor that regulates the expression of many genes, thereby eliciting a myriad of cellular responses, most of them culminate in an anti-tumorigenic effect [1]. Recently, the concept of p53 as a regulator of metabolism has emerged with various metabolic pathways found to be regulated by p53 in an anti-tumorigenic effort [2,3].To comprehensively describe the effect of p53 on liver-related metabolic pathways, we performed two consecutive high-throughput analyses. We evaluated the global alterations in gene expression in liver-derived HepG2 cells following two reciprocal manipulations in p53 status. First, we down-regulated p53 levels in a group of HepG2 cells by stably expressing short hairpin RNA targeting p53 (termed HepG2sh-p53) while the control group expressed a non-relevant short hairpin RNA (termed HepG2sh-con). Second, we treated the cells with Nutlin-3a, a