The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation.Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated.Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources.Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s.Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx.Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect.Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes. Results Fasting-refeeding acutely activates hepatic Xbp1s and the UPR.To define the role of Xbp1s in the postprandial adaptation, we performed a time course study of fasting-refeeding.Xbp1s mRNA increased more than 10-fold within the first hour of refeeding (Figure 1, A and B), overlapping with its pattern of protein expression (Figure 1C).This upregulation was transient.By 3 hours of refeeding, Xbp1s levels dropped to near basal values, only to increase again after 8 hours, when the animals started to eat again (Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/JCI62819DS1).In addition to Xbp1s, other components of the UPR were also activated during the postprandial state.These include the induction of phosphorylation of eIF2α and the transcriptional activation of Bip, Atf6, CHOP, ERdj4, and Edem1 (Supplemental Figure 1, B-D).The ratio of Xbp1s to Xbp1 does not reflect the absolute increase in Xbp1 splicing, since unspliced Xbp1 is continually transcriptionally replenished.Therefore, even though the Xbp1s/Xbp1 ratio is not Conflict of interest:The authors have declared that no conflict of interest exists.