The role of X-box binding protein 1 in the hepatic response to refeeding in mice

Abstract

Refeeding mice after a prolonged fast is a potent stimulus of hepatic lipogenesis, but is also associated with induction of the hepatic unfolded protein response (UPR). The X-box binding protein 1 (Xbp1), a key regulator of the adaptive UPR, transcriptionally activates hepatic lipogenesis genes. We therefore determined whether hepatic Xbp1 mediates the hepatic lipogenic response to refeeding. Mice bearing a hepatocyte-specific deletion of Xbp1 and littermate controls were fasted overnight, followed by refeeding for up to 6 h. Among control mice, refeeding induced hepatic expression of activated Xbp1 and, as expected, induced hepatic expression of genes controlling de novo lipogenesis of fatty acids. Unexpectedly, deletion of hepatic Xbp1 allowed for normal induction of hepatic lipogenesis genes, yet impaired translation of SREBP1c and its targets in response to refeeding. Impaired protein translation was associated with enhanced postprandial activation of the global translational arrest protein, eukaryotic initiation factor 2α, among mice lacking hepatic Xbp1 Deletion of hepatic Xbp1 prevented postprandial induction of genes regulating protein folding and processing and shifted the pattern of postprandial UPR activation to favor proapoptotic signals. We conclude that activation of hepatic Xbp1 in the postprandial states serves the dual roles of restoring postprandial hepatic lipogenesis and proteostasis.