Hepatic glucose production (HGP) is crucial for maintaining systemic glucose homeostasis. Dysregulated HGP is the hallmark of type-2 diabetes (T2D). During fasting, hepatocyte nuclear factor 4 alpha (HNF4A) acts in concert with coactivators to stimulate transcription of key gluconeogenic genes leading to gluconeogenesis program. It is found that the evolutionarily conserved H19 lncRNA stimulates HGP in part by decreasing Hnf4? promoter methylation and promoting its expression. While fasting temporally increases hepatic H19, its level is chronically elevated in diabetic mice, consistent with previously reported chronic H19 elevation in liver of diabetic patients. It is also noticed that glucagon upregulates H19, consistent with glucagon-induced hepatic gluconeogenesis during fasting and with observations of chronic hyperglucagonemia in T2D patients. Based on these findings it is hypothesized that H19 functions as a novel regulator of HGP by targeting Hnf4? at the epigenetic level. To test this hypothesis, the molecular mechanism by which H19 alters Hnf4? expression will be dissected and the signal transduction pathway leading to glucagon-induced H19 upregulation will be investigated. Despite the identification of numerous lncRNAs in the human genome, the physiological role of the vast majority has remained elusive. In the mouse, a number of lncRNAs have been shown to play important roles in metabolism, yet no human counterparts have been found so far. Uncovering novel pathways mediated by the evolutionarily conserved H19 in HGP regulation holds the potential of discovering new therapeutic targets for diabetes and other metabolic diseases.
We have discovered that the H19 lncRNA stimulates hepatic glucose production by modulating expression of HNF4A, a master transcriptional regulator of gluconeogenesis. We will dissect the molecular interactions and signal transduction pathways underlying the H19-mediated regulation of gluconeogenesis, with the expectation of discovering new therapeutic targets for diabetes and other metabolic diseases.
