studies

344A AASLD ABSTRACTS HEPATOLOGY, October, 2015
257
Hepatic XBP1 deletion promotes endoplasmic reticulum
stress-induced liver injury and apoptosis
Shantel Olivares, Anne Henkel; Medicine, Northwestern University,
Chicago, IL
Endoplasmic reticulum (ER) stress triggers activation of the
unfolded protein response (UPR), a highly conserved signaling
cascade that functions to alleviate stress and promote cell survival.
If, however, the cell is unable to restore homeostasis, the
UPR activates pathways that promote apoptotic cell death. The
molecular mechanisms governing this critical transition from restoration
of homeostasis to initiation of apoptosis remain poorly
understood. We aim to determine the role of hepatic XBP1, a
key regulator of the UPR, in controlling cell fate in response
to ER stress. Liver-specific XBP1 knockout mice (XBP1 LKO ) and
XBP1 fl/fl littermate controls were subjected to varying levels and
duration of pharmacologic ER stress. XBP1 LKO mice and XBP1 fl/
fl
controls showed robust and equal induction of the UPR acutely
as evidenced by equivalent hepatic expression of Grp78/BIP,
CHOP, and ATF4 six hours after exposure to pharmacologic
ER stress. By 72 hours, XBP1 fl/fl control mice showed complete
resolution of UPR activation and no liver injury suggesting complete
restoration of homeostasis. Conversely, XBP1 LKO mice
showed ongoing UPR activation at 3 and 7 days after induction
of ER stress associated with progressive liver injury histologically.
Consistent with enhanced hepatic injury, plasma ALT
levels were markedly elevated in XBP1 LKO mice at days 3 and 7
(283±41 vs 49±12 IU/L at day 3 and 217±3 vs 47±11 IU/L at
day 7 vs XBP1 fl/fl controls, p