Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α

Abstract

X-box binding protein-1 (XBP1) is a transcription factor that plays a central role in controlling cellular responses to endoplasmic reticulum (ER) stress. Under stress conditions, the transcriptionally active form of XBP1 is generated by unique splicing of Xbp1 mRNA by the ER-resident protein inositol-requiring enzyme-1 (IRE1). Genetic deletion of XBP1 has multiple consequences: some resulting from the loss of the transcription factor per se, and others related to compensatory upstream activation of IRE1. The objective of the current study was to investigate the effects of XBP1 deletion in adult mouse liver and determine to what extent they are direct or indirect. XBP1 was deleted specifically from hepatocytes in adult Xbp1fl/fl mice using AAV8-Transthyretin-Cre (Xbp1{Delta}hep). Xbp1{Delta}hep mice exhibited no liver disease at baseline, but developed acute biochemical and histologic liver injury in response to a dietary challenge with fructose for 4 wk. Fructose-mediated liver injury in Xbp1{Delta}hep mice coincided with heightened IRE1 activity, as demonstrated by cJun phosphorylation and regulated IRE1 -dependent RNA decay (RIDD). Activation of eIF2 was also evident, with associated up-regulation of the pro-apoptotic molecules CHOP, BIM and PUMA. To determine whether the adverse consequences of liver-specific XBP1 deletion were due to XBP1 loss or heightened IRE1 activity, we repeated a fructose challenge in mice with liver-specific deletion of both XBP1 and IRE1 (Xbp1{Delta}hep;IRE1{Delta}hep). Xbp1{Delta}hep;IRE1{Delta}hep mice were protected from fructose-mediated liver injury and failed to exhibit any of the signs of ER stress seen in mice lacking XBP1 alone. The protective effect of IRE1 deletion persisted even with long-term exposure to fructose. Xbp1{Delta}hep mice developed liver fibrosis at 16 wk, but Xbp1{Delta}hep;IRE1{Delta}hep mice did not. Overall, the results indicate that the deleterious effects of hepatocyte-specific XBP1 deletion are due primarily to hyperactivation of IRE1. They support further exploration of IRE1 as a contributor to acute and chronic liver diseases.