Deficiency of manganese superoxide dismutase in hepatocytes disrupts zonated gene expression in mouse liver.
The liver acinus displays a physiological periportal to perivenous oxygen gradient. This gradient was implicated to use reactive oxygen species (ROS) as mediators for the zonal gene expression. Mitochondria use oxygen and produce ROS, therefore they may contribute to the zonation of gene expression. To further elucidate this, we used the Cre-loxP system to generate a hepatocyte-specific null mutation of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) in mice. We found that ROS levels were enhanced in livers of MnSOD(-/-) mice which were reduced in size and displayed signs of liver failure such as intracellular protein droplets, increased apoptotic bodies and Bax levels as well as multinuclear hepatocytes. Further, the zonation of glutamine synthetase, glucokinase and phosphoenolpyruvate carboxykinase was no longer preserved. We conclude that deficiency of mitochondrial MnSOD initiates a dysregulation of zonated gene expression in liver.
Lenart
Jacek
J
Faculty of Chemistry, Department of Biochemistry, Erwin-Schrödinger-Strasse, University of Kaiserslautern, 67663 Kaiserslautern, Germany.
Dombrowski
Frank
F
Görlach
Agnes
A
Kietzmann
Thomas
T
D000818:Animals; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D014018:Tissue Distribution
D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D010100:Oxygen