title: High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways.
abstract: High fat diet (HFD) is closely linked to a variety of health issues including fatty liver. Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated carboxylic acid, also causes liver injury. The present study investigated the possible interactions between high fat diet and PFOA in induction of liver injury. Mice were pair-fed a high-fat diet (HFD) or low fat control with or without PFOA administration at 5 mg/kg/day for 3 weeks. Exposure to PFOA alone caused elevated plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels and increased liver weight along with reduced body weight and adipose tissue mass. HFD alone did not cause liver damage, but exaggerated PFOA-induced hepatotoxicity as indicated by higher plasma ALT and AST levels, and more severe pathological changes including hepatocyte hypertrophy, lipid droplet accumulation and necrosis as well as inflammatory cell infiltration. These additive effects of HFD on PFOA-induced hepatotoxicity correlated with metabolic disturbance in liver and blood as well as up-regulation of hepatic proinflammatory cytokine genes. Metabolomic analysis demonstrated that both serum and hepatic metabolite profiles of PFOA, HFD, or HFD-PFOA group were clearly differentiated from that of controls. PFOA affected more hepatic metabolites than HFD, but HFD showed positive interaction with PFOA on fatty acid metabolites including long chain fatty acids and acylcarnitines. Taken together, dietary high fat potentiates PFOA-induced hepatic lipid accumulation, inflammation and necrotic cell death by disturbing hepatic metabolism and inducing inflammation. This study demonstrated, for the first time, that HFD increases the risk of PFOA in induction of hepatotoxicity.
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina, United States of America.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tan
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Xie
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Sun
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Peter
authors.initials: P
authors.lastname: Qiao
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002210:Caprylates / Q000633:toxicity*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005466:Fluorocarbons / Q000633:toxicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D002210:Caprylates; D005227:Fatty Acids; D005466:Fluorocarbons; D014280:Triglycerides; C023036:perfluorooctanoic acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase