Differential splicing analysis of liver-specific A1cf knock-out mice

The regulation of hepatic gene expression has been extensively studied at the transcriptional level, however the control of metabolism through posttranscriptional gene regulation by RNA binding proteins in physiological and disease states are less understood. We identified a major role for the hormone-sensitive RNA binding protein (RBP) APOBEC1 complementation factor (A1CF) in the generation of hepatocyte-specific and alternatively spliced transcripts. Among these transcripts are isoforms for the dominant and high-affinity fructose-metabolizing Ketohexokinase C and glycerol kinase, two key metabolic enzymes that are linked to hepatic gluconeogenesis and found to be markedly reduced upon hepatic ablation of A1cf. Consequently, mice lacking A1CF exhibit improved glucose tolerance and are protected from fructose-induced hyperglycemia, hepatic steatosis and development of obesity. Together our results identify a novel function of A1CF as a regulator of alternative splicing of a subset of genes influencing insulin sensitivity as well as fructose and glycerol metabolism.