Activation of peroxisome proliferator-activated receptor α ameliorates perfluorododecanoic acid-induced production of reactive oxygen species in rat liver

Abstract

Perfluorododecanoic acid (PFDoA) is a ubiquitous environmental pollutant known to cause hepatocellular hypertrophy; however, the mechanisms of hepatotoxicity remain poorly understood. In this study, male rats were exposed to 0, 0.05, 0.2 and 0.5 mg/kg/day of PFDoA for 110 days. After two-dimensional differential gel electrophoresis and MALDI-TOF/TOF analysis, 73 differentially expressed proteins involved in lipid metabolism, inflammation, stress response and other functions were successfully identified. Among them, six significantly changed proteins (CTE1, MTE1, HADHA, ECH1, ALDH2 and CPS1) were found to be regulated by peroxisome proliferator-activated receptor alpha (PPARα). The anti-oxidant enzyme activity assays of superoxide dismutase and glutathione peroxidase and the content of thiobarbituric acid-reactive substances in the liver implied that PFDoA caused oxidative stress. The mRNA levels of PPARα in rat primary hepatocytes were knocked down by lentivirus-mediated RNAi. Furthermore, targeted protein levels of CTE1 and MTE1 were down-regulated, while those of HADHA, ALDH2 and CPS1 were up-regulated. After PFDoA exposure, however, the targeted protein levels of CTE1 and ALDH2 increased compared with those of the knockdown untreated group. The reactive oxygen species (ROS) content in rat hepatocytes assayed by flow cytometry significantly increased in the PPARα knockdown groups, consistent with the PPARα antagonist GW6471- and agonist WY14643-treated groups. These results strongly suggested that PPARα played an important role in suppressing ROS content in hepatocytes following PFDoA exposure.

Disposition of perfluorododecanoic acid in male rats after oral administration

“…Kato et al (2015) have reported that hypertrophy, necrosis, and inflammatory cholestasis were observed in the liver after chronic administration of PFDoA at a dose of 0.5 and 2.5 mg/kg for 42-47 days in male rats. Hepatotoxicity of PFDoA has been shown to be due to production of reactive oxygen species in rats (Liu et al, 2016). Our present study showed high accumulation of PFDoA in the liver.…”

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity

“…FAO-relevant genes [except enoyl - CoA hydratase 3 - hydroxyacyl CoA dehydrogenase (Ehhadh), carnitine O - acetyltransferase (Crat) and solute carrier family 25 member 20 (Slc25a20) ] were significantly reduced in mouse renal tissue following zoledronate treatment (Fig. 4 g) (Kang et al 2015 ; Li et al 2008 ; Polinati et al 2009 ; Liu et al 2016 ), pointing to defects in FAO in mouse kidney by zoledronate administration. Long-chain FAs are the main energy source for renal tubular epithelial cells (Kang et al 2015 ), which enter the cells mostly through several membrane proteins, including FA carrier CD36 and FA transport proteins (Verhulst et al 2015 ).…”

Targeting Hepatic Protein Carbonylation and Oxidative Stress Occurring on Diet-Induced Metabolic Diseases through the Supplementation with Fish Oils

“…EPA and DHA also displayed an important effect on proteins of nitrogen metabolism. Among them, Cps1, which is a known target of carbonylation in the liver [ 30 ] and Ass1, which acts in the ammonia detoxification and whose expression is submitted to both hormonal and nutritional regulation. The carbonylation of liver Ass1 observed under HFHS diets could affect the optimal removal of toxic ammonia, and finally, would lead to metabolic disturbances as hyperammonemia [ 31 ].…”