title: Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach.
abstract: 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.
authors: Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili , Reus, Spain.
authors: Anabel
authors: A
authors: García-Heredia
authors: Elizabeth
authors: E
authors: Kensicki
authors: Robert P
authors: RP
authors: Mohney
authors: Anna
authors: A
authors: Rull
authors: Iris
authors: I
authors: Triguero
authors: Judit
authors: J
authors: Marsillach
authors: Carmen
authors: C
authors: Tormos
authors: Bharti
authors: B
authors: Mackness
authors: Michael
authors: M
authors: Mackness
authors: Diana M
authors: DM
authors: Shih
authors: Juan
authors: J
authors: Pedro-Botet
authors: Jorge
authors: J
authors: Joven
authors: Guillermo
authors: G
authors: Sáez
authors: Jordi
authors: J
authors: Camps
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002784:Cholesterol / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009963:Orotic Acid / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D009963:Orotic Acid; D002784:Cholesterol; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse; D005978:Glutathione; D005947:Glucose