Abstract
Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol.
Highlights
The liver plays a critical role in lipid homeostasis where various metabolic enzymes and proteins work in tandem to balance fat levels in the body (Figure 1A)
Livers of obese JCR rats exposed to Northern Contaminant Mixture (NCM) (OWH and obese:ethanol:high dose (OEH)) weighed more than livers exposed to vehicle solvent (OWV and OEV respectively) (Figure 1B)
It has been firmly established that prolonged exposure to industrial chemicals and contaminants can result in Non-alcoholic fatty liver disease (NAFLD) and NASH and that Northern populations can be exposed to high amounts of environmental toxins for prolonged periods [15,24]
Summary
The liver plays a critical role in lipid homeostasis where various metabolic enzymes and proteins work in tandem to balance fat levels in the body (Figure 1A). Lipid homeostasis is maintained by de novo lipid biosynthesis (lipogenesis and cholesterol biosynthesis) and mitochondrial b-oxidation [1]. Lipid degradation occurs in mitochondria and results in the production of ATP [2]. On the other hand, involves the commitment of acetyl-CoA produced from citric acid to the genesis of short, medium, and long-chain fatty acids which are esterified to produce triglycerides [3]. Lipid biosynthesis and degradation do not operate simultaneously since it would lead to the futile cycling of acetyl-CoA and the loss of energy. Instead both pathways are activated and deactivated, respectively, in response to the changing energy demands and nutrient status of the body
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