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.