Paraoxonase-1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach
Por:
Garcia-Heredia, A, Kensicki, E, Mohney, R, Rull, A, Triguero, I, Marsillach, J, Tormos, C, Mackness, B, Mackness, M, Shih, D, Pedro-Botet, J, Joven, J, Saez, G and Camps, J
Publicada:
1 abr 2013
Resumen:
Oxidative stress is a determinant of liver steatosis and the progression to more severe forms of disease. The present study investigated the effect of paraoxonase-1 (PON1) deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. We performed nontargeted metabolomics on liver tissues from 8 male PON1-deficient mice and 8 wild-type animals fed a high-fat, high-cholesterol diet for 22 weeks. We also measured 8-oxo-20-deoxyguanosine, reduced and oxidized glutathione, malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in 83.3% of the PON1-deficient animals (P < 0.001). The metabolomic assay included 322 biochemical compounds, 169 of which were significantly decreased and 16 increased in PON1-deficient mice. There were significant increases in lipid peroxide concentrations and oxidative stress markers. We also found decreased glycolysis and the Krebs cycle. The urea cycle was decreased, and the pyrimidine cycle had a significant increase in orotate. The pathways of triglyceride and phospholipid synthesis were significantly increased. We conclude that PON1 deficiency is associated with oxidative stress and metabolic alterations leading to steatosis in the livers of mice receiving a high fat high-cholesterol diet.
Filiaciones:
Garcia-Heredia, A:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
Kensicki, E:
Metabolon Inc, Durham, NC USA
Mohney, R:
Metabolon Inc, Durham, NC USA
Rull, A:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
Triguero, I:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
Marsillach, J:
Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA
Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
Tormos, C:
Univ Valencia, Dept Biochem & Mol Biol, Fac Med CIBERON, Serv Clin Anal CDBI HGUV, E-46003 Valencia, Spain
Mackness, B:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
Mackness, M:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
Shih, D:
Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA
Pedro-Botet, J:
Hosp Mar, Med Interna Serv, Barcelona, Spain
Joven, J:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
:
Univ Valencia, Dept Biochem & Mol Biol, Fac Med CIBERON, Serv Clin Anal CDBI HGUV, E-46003 Valencia, Spain
Camps, J:
Univ Rovira & Virgili, Inst Invest Sanitaria Pere Virgili, Hosp Univ St Joan, Unitat Recerca Biomed, E-43201 Reus, Spain
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