Increased oxidative stress is associated with balanced increases in hepatocyte apoptosis and proliferation in glycerol-3-phosphate acyltransferase-1 deficient mice.
The absence of mouse mitochondrial glycerol-3-phosphate acyltransferase-1 (Gpat1-/-) increases the amount of arachidonate in liver phospholipids and increases beta-hydroxybutyrate and acyl-carnitines, suggesting an elevated rate of liver fatty acid oxidation. We asked whether these alterations might increase reactive oxygen species (ROS), apoptosis, or hepatocyte proliferation. Compared to wildtype controls, liver mitochondria from Gpat1-/- mice showed a 20% increase in the rate of ROS production and a markedly increased sensitivity to the induction of the mitochondrial permeability transition. Mitochondrial phosphatidylethanolamine and phosphatidylcholine from Gpat1-/- liver contained 21% and 67% more arachidonate, respectively, than wildtype controls, and higher amounts of 4-hydroxynonenal, a product of arachidonate peroxidation. Oxidative stress was associated with an increase in apoptosis, and with 3-fold and 15-fold higher TUNEL positive cells in liver from young and old Gpat1-/- mice, respectively, compared to age-matched controls. Compared to controls, bromodeoxyuridine labeling was 50% and 7-fold higher in livers from young and old Gpat1-/- mice, respectively, but fewer glutathione-S-transferase positive cells were present. Thus, Gpat1-/- liver exhibits increased oxidative stress and sensitivity of the mitochondrial permeability transition pore, and a balanced increase in apoptosis and proliferation.
Hammond
Linda E
LE
Department of Nutrition, CB#7461, 2301 Michael Hooker Research Building, Columbia Street, University of North Carolina, Chapel Hill, NC 27599, USA.
Albright
Craig D
CD
He
Lihua
L
Rusyn
Ivan
I
Watkins
Steven M
SM
Doughman
Scott D
SD
Lemasters
John J
JJ
Coleman
Rosalind A
RA
D000367:Age Factors; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000447:Aldehydes; D005227:Fatty Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010743:Phospholipids; D017382:Reactive Oxygen Species; D005992:Glycerol-3-Phosphate O-Acyltransferase; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal