4 research outputs found
Paraoxonase‑1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach
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 (<i>P</i> < 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
Polymorphisms Cyclooxygenase-2 -765G>C and Interleukin-6 -174G>C Are Associated with Serum Inflammation Markers in a High Cardiovascular Risk Population and Do Not Modify the Response to a Mediterranean Diet Supplemented with Virgin Olive Oil or Nuts
Inflammation is involved in cardiovascular diseases. Some studies have found that the Mediterranean diet (MD) can reduce serum concentrations of inflammation markers. However, none of these studies have analyzed the influence of genetic variability in such a response. Our objective was to study the effect of the -765G>C polymorphism in the cyclooxygenase-2 (COX-2) gene and the -174G>C polymorphism in the interleukin-6 (IL-6) gene on serum concentrations of IL-6, C-reactive protein, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 as well as their influence on the response to a nutritional intervention with MD. An intervention study in a high cardiovascular risk Mediterranean population (314 men and 407 women) was undertaken. Participants were randomly assigned to consume a low-fat control diet or a MD supplemented with virgin olive oil or nuts. Measures were obtained at baseline and after a 3-mo intervention period. At baseline, the COX-2 -765G>C polymorphism was associated with lower serum IL-6 (5.85 ± 4.82 in GG vs. 4.74 ± 4.14 ng/L in C-allele carriers; P = 0.002) and ICAM-1 (265.8 ± 114.8 in GG vs. 243.0 ± 107.1 μg/L in C-carriers; P = 0.018) concentrations. These differences remained significant after multivariate adjustment. The IL-6 -174G>C polymorphism was associated with higher (CC vs. G-carriers) serum ICAM-1 concentrations in both men and women and with higher serum IL-6 concentrations in men. Following the dietary intervention, no significant gene x diet interactions were found. In conclusion, although COX-2 -765G>C and IL-6 -174G>C polymorphisms were associated with inflammation, consuming a MD (either supplemented with virgin olive oil or nuts) reduced the concentration of inflammation markers regardless of these polymorphisms.Supported by grants PI052368, PI051458, PI042234, PI051839, PI052584, PI040233, PI070240, PI070954, G03/140, RD06/0045/0000, RD06/0045/0001, CNIC06, and CB06/03 from the Instituto de Salud Carlos III, Madrid, Spain; by grants GRUPOS2004-43 and ACOMP06109 from the Generalitat Valenciana, Spain; and by grant PI41/2005 from the Navarra Government, Spain.Peer reviewe