BACKGROUND & AIMS: Liver cell hydration is a major determinant of proteolysis control; however, the underlying mechanisms are unknown. METHODS: The role of mitogen-activated protein kinases for proteolysis control was studied in perfused rat liver. RESULTS: Hyposmolarity led to a rapid activation of Erk-2 and p38(MAPK), but not of c-Jun-N-terminal kinase 1. Likewise, isosmotic cell swelling induced by insulin, ethanol, or glutamine/glycine activated p38(MAPK). Inhibition of hyposmotic Erk activation by pertussis or cholera toxin, erbstatin, or genistein had no effect on the swelling-induced inhibition of proteolysis. Likewise, wortmannin, rapamycin, and okadaic acid were ineffective, but proteolysis recovery from hyposmotic inhibition was okadaic acid sensitive. SB203580, an inhibitor of p38(MAPK), abolished both the antiproteolytic effect of hyposmotic cell swelling and the hyposmolarity-induced inhibition of autophagic vacuole formation. Also, the antiproteolytic effect of isotonic cell swelling induced by ethanol, glutamine/glycine, or insulin was abolished by SB203580, but not the swelling potency of these agents. SB203580 had no effect on the cell hydration-independent control of proteolysis exerted by NH4Cl, asparagine, or phenylalanine. CONCLUSIONS: The data suggest an important role of p38(MAPK) in the regulation of autophagic proteolysis by cell volume in liver.
BACKGROUND & AIMS: Liver cell hydration is a major determinant of proteolysis control; however, the underlying mechanisms are unknown. METHODS: The role of mitogen-activated protein kinases for proteolysis control was studied in perfused rat liver. RESULTS: Hyposmolarity led to a rapid activation of Erk-2 and p38(MAPK), but not of c-Jun-N-terminal kinase 1. Likewise, isosmotic cell swelling induced by insulin, ethanol, or glutamine/glycine activated p38(MAPK). Inhibition of hyposmotic Erk activation by pertussis or cholera toxin, erbstatin, or genistein had no effect on the swelling-induced inhibition of proteolysis. Likewise, wortmannin, rapamycin, and okadaic acid were ineffective, but proteolysis recovery from hyposmotic inhibition was okadaic acid sensitive. SB203580, an inhibitor of p38(MAPK), abolished both the antiproteolytic effect of hyposmotic cell swelling and the hyposmolarity-induced inhibition of autophagic vacuole formation. Also, the antiproteolytic effect of isotonic cell swelling induced by ethanol, glutamine/glycine, or insulin was abolished by SB203580, but not the swelling potency of these agents. SB203580 had no effect on the cell hydration-independent control of proteolysis exerted by NH4Cl, asparagine, or phenylalanine. CONCLUSIONS: The data suggest an important role of p38(MAPK) in the regulation of autophagic proteolysis by cell volume in liver.
Authors: E Keil; R Höcker; M Schuster; F Essmann; N Ueffing; B Hoffman; D A Liebermann; K Pfeffer; K Schulze-Osthoff; I Schmitz Journal: Cell Death Differ Date: 2012-10-12 Impact factor: 15.828