title: Role of bile acids in liver injury and regeneration following acetaminophen overdose.
abstract: Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)-induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)-containing diet for bile acid depletion, or a 0.2% cholic acid (CA)-containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet-fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Bharat
authors.initials: B
authors.lastname: Bhushan
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Prachi
authors.initials: P
authors.lastname: Borude
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Genea
authors.initials: G
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Chad
authors.initials: C
authors.lastname: Walesky
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Joshua
authors.initials: J
authors.lastname: Cleveland
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas. Electronic address: uapte@kumc.edu.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D002792:Cholestyramine Resin / Q000494:pharmacology; D062787:Drug Overdose / Q000473:pathology* / Q000503:physiopathology*; D005247:Feeding Behavior / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D012333:RNA, Messenger; C108526:fibroblast growth factor 15, mouse; D002792:Cholestyramine Resin; D000082:Acetaminophen; D005346:Fibroblast Growth Factors