title: Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.
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 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.
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada; Departments of Biology and Chemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada; Departments of Biology and Chemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Florian
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Qixuan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Petrov
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Coughlan
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada; Departments of Biology and Chemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Mahemuti
authors.initials: M
authors.lastname: Laziyan
authors.affiliation: Scientific Support Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Caldwell
authors.affiliation: Scientific Support Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lalande
authors.affiliation: Scientific Support Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Patry
authors.affiliation: Nutrition Research Division, Bureau of Nutritional Sciences, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Gagnon
authors.affiliation: Nutrition Research Division, Bureau of Nutritional Sciences, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Kurtis
authors.initials: K
authors.lastname: Sarafin
authors.affiliation: Departments of Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Truong
authors.affiliation: Departments of Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Hing Man
authors.initials: HM
authors.lastname: Chan
authors.affiliation: Nutrition Research Division, Bureau of Nutritional Sciences, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Nimal
authors.initials: N
authors.lastname: Ratnayake
authors.affiliation: Hazard Identification Division, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Nanqin
authors.initials: N
authors.lastname: Li
authors.affiliation: Departments of Biology and Chemistry, Carleton University, Ottawa, Ontario, Canada.
authors.forename: William G
authors.initials: WG
authors.lastname: Willmore
authors.affiliation: Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Jin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000009:adverse effects*; D000431:Ethanol / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D004930:Inuit; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011919:Rats, Inbred Strains
chemical_list: D004785:Environmental Pollutants; D000431:Ethanol; D000255:Adenosine Triphosphate; D002784:Cholesterol