Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis

Plasminogen activator inhibitor 1 (PAI-1) is a stress-responsive gene that is highly induced in nonalcoholic steatohepatitis (NASH). Endoplasmic reticulum (ER) stress is a salient feature of NASH, yet it is unknown whether ER stress contributes to hepatic PAI-1 induction in this disorder. Therefore, we aimed to (a) establish the role of ER stress in the regulation of hepatic Pai-1 expression, and (b) determine whether induction of Pai-1 in murine NASH is driven by ER stress. Hepatic Pai-1 expression was measured in C57BL/6 J mice and human HepG2 cells subjected to acute or prolonged pharmacologic ER stress. We found that hepatic Pai-1 expression was acutely suppressed in murine liver in response to severe ER stress followed by marked induction during the recovery phase of the ER stress response. Hepatic Pai-1 expression was induced in response to prolonged low-grade ER stress in mice. Induction of PAI-1 by ER stress in HepG2 cells was prevented by pharmacologic inhibition of MEK1/ERK signaling or by siRNA-mediated knockdown of XBP1, mediators of the recovery response to ER stress. Inhibiting ER stress with 4-phenylbutyric acid prevented hepatic Pai-1 induction in mice with diet-induced steatohepatitis. We conclude that hepatic Pai-1 is induced by ER stress via a pathway involving XBP1 and MEK1/ERK signaling, and induction of hepatic Pai-1 in murine NASH is mediated by ER stress. These data implicate ER stress as a novel mechanistic link between Pai-1 induction and NASH.