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.

Açai (Euterpe oleracea Mart.) Upregulates Paraoxonase 1 Gene Expression and Activity with Concomitant Reduction of Hepatic Steatosis in High‐Fat Diet‐Fed Rats

“…The HF rats also showed reduced serum and liver PON1 activity. These findings corroborate with García-Heredia et al [25] that showed that PON-deficient mice fed a high-fat high-cholesterol diet presented significant alterations in liver tissues, such as increased hepatic steatosis and the expression of makers of oxidative stress and inflammation.…”

“…PON1 levels significantly decreased in serum of patients with chronic liver diseases such as NAFLD, hepatitis, and cirrhosis [13, 24]. More relevantly, PON1-deficient mice fed a high-fat high-cholesterol diet showed histological alterations in the liver, suggesting that PON1 plays a major role in protection against oxidative stress on diet-induced fatty liver [25]. …”

Inflammation, Infection, Cancer and All That…The Role of Paraoxonases

“…For example, PON1 deficient mice have been shown to be more susceptible to lipoprotein oxidation, inflammation, atherosclerosis [12, 13, 27], and hepatic steatosis [28], whereas PON1 transgenic mice over-expressing human PON1 are more resistant to inflammation and atherosclerosis [14]. PON1 has been shown to prevent LDL oxidation in vitro [18, 19] and decreased levels of PON1 are associated with increased risk for cardiovascular disease in humans [7, 29–32].…”

Paraoxonase-1 (PON1) induces metastatic potential and apoptosis escape via its antioxidative function in lung cancer cells

“…PON1-deficient mice are found to have decreased glycolysis [18]. Glucose-enrichment invariably regulated PON1 expression while glucose-starvation recovered the expression in A549 cells (Figure 6A, 6B) while no regulation was observed in L132 cells (data not shown).…”