Non-alcoholic fatty liver disease (NAFLD) is affecting up to one-third of the general population in western countries. While the major cause of NAFLD is related to an unhealthy lifestyle, recent evidence has shown a role of chemical exposure in the induction and progression of NAFLD. Perfluorooctanoate (PFOA) is a ubiquitous environmental contaminant that exerts its hepatotoxicity mainly through the activation of peroxisome proliferator-activated receptor α (PPARα). We examined how PFOA might affect the progression of NAFLD and whether a preexisting fatty liver intensified or alleviated the effects of PFOA in the livers. As such, male C57BL/6 mice were fed with a low-fat control diet (CD) or a high fat diet (HFD) for 16 weeks to model normal or steatotic livers, respectively. Mice were then administered with PFOA (1mg/kg/d) by oral gavage for an additional 2, 8, and 16 weeks. Dietary treatment was continued throughout the whole study. We found HFD induced hepatic steatosis, lobular inflammation, and progressive fibrosis in mice. As expected, PFOA activated PPARα, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), regardless of the diet. Gene expression analysis showed the interactions between HFD and PFOA on hepatic nuclear receptors were time-dependent. Hepatocytes growth as measured by DNA synthesis and cell growth genes induced by PFOA were exacerbated in the HFD group after 2 weeks, along with the enhanced activation of PPARα. In contrast, PFOA decreased the severity of hepatic steatosis. In HFD-fed mice, the hepatic triglyceride levels were reduced to 75%, 47%, and 40%, after 2, 8, and 16 weeks of PFOA treatment, respectively, compared to vehicle controls. Transcriptomic analysis showed the preexisting NAFLD enhanced PFOA related lipid oxidation pathways in mice. HFD induced hepatic fibrosis as measured by collagen staining and fibrosis gene markers were also attenuated by PFOA. Taken together, this study demonstrated that the preexisting NAFLD might impact on many biological effects induced by PFOA and thus need to be carefully considered as a factor in risk assessment.
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