Hepatic X-Box Binding Protein 1 and Unfolded Protein Response Is Impaired in Weanling Mice With Resultant Hepatic Injury

Background and aims: The unfolded protein response (UPR) is a coordinated cellular response to endoplasmic reticulum (ER) stress that functions to maintain cellular homeostasis. When ER stress is unresolved, the UPR can trigger apoptosis. Pathways within the UPR influence bile acid metabolism in adult animal models and adult human liver diseases, however, the UPR has not been studied in young animal models or pediatric liver diseases. In this study we sought to determine whether weanling age mice had altered UPR activation compared with adult mice, which could lead to increased bile acid-induced hepatic injury.

Approach and results: We demonstrate that after 7 days of cholic acid (CA) feeding to wild-type animals, weanling age mice have a 2-fold greater serum alanine aminotransferase (ALT) levels compared with adult mice, with increased hepatic apoptosis. Weanling mice fed CA have increased hepatic nuclear X-box binding protein 1 spliced (XBP1s) expression, but cannot increase expression of its protective downstream target's ER DNA J domain-containing protein 4 and ER degradation enhancing α-mannoside. In response to tunicamycin induced ER stress, young mice have blunted expression of several UPR pathways compared with adult mice. CA feeding to adult liver-specific XBP1 knockout (LS-XBP1^-/- ) mice, which are unable to resolve hepatic ER stress, leads to increased serum ALT and CCAAT/enhancer binding homologous protein, a proapoptotic UPR molecule, expression to levels similar to CA-fed LS-XBP1^-/- weanlings.

Conclusions: Weanling mice have attenuated hepatic XBP1 signaling and impaired UPR activation with resultant increased susceptibility to bile acid-induced injury.