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
ISSN: 15353907





JOURNAL OF PROTEOME RESEARCH
Editorial
American Chemical Society, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA, Estados Unidos America
Tipo de documento: Article
Volumen: 12 Número: 4
Páginas: 1946-1955
WOS Id: 000317327500037
ID de PubMed: 23448543

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