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 to 10%
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.