Increased oxidative stress is associated with balanced increases in hepatocyte apoptosis and proliferation in glycerol-3-phosphate acyltransferase-1 deficient mice |
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Authors: | Hammond Linda E Albright Craig D He Lihua Rusyn Ivan Watkins Steven M Doughman Scott D Lemasters John J Coleman Rosalind A |
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Institution: | Department of Nutrition, CB#7461, 2301 Michael Hooker Research Building, Columbia Street, University of North Carolina, Chapel Hill, NC 27599, USA. |
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Abstract: | 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. |
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Keywords: | BrdU 5-bromo-2′-deoxyuridine CCCP carbonyl cyanide p-chlorophenylhydrazone carboxy-DCFDA (5-and-6)-chloromethyl-2′ 7′-dichlorodihydrofluorescein diacetate acetyl ester GST glutathione transferase 4-HNE 4-hydroxy-2-nonenal GPAT1 mitochondrial glycerol-3-phosphate acyltransferase-1 MPT mitochondrial permeability transition PC phosphatidylcholine PE phosphatidylethanolamine PS phosphatidylserine ROS reactive oxygen species TMRM tetramethylrhodamine methyl ester TUNEL terminal dUTP nick end labeling |
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