Role of bile acids in liver injury and regeneration following acetaminophen overdose

Am J Pathol. 2013 Nov;183(5):1518-1526. doi: 10.1016/j.ajpath.2013.07.012. Epub 2013 Sep 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects*
  • Animals
  • Bile Acids and Salts / metabolism*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / pathology*
  • Chemical and Drug Induced Liver Injury / physiopathology*
  • Cholestyramine Resin / pharmacology
  • Drug Overdose / pathology*
  • Drug Overdose / physiopathology*
  • Feeding Behavior / drug effects
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation / drug effects
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Regeneration* / drug effects
  • Liver Regeneration* / genetics
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Bile Acids and Salts
  • RNA, Messenger
  • fibroblast growth factor 15, mouse
  • Cholestyramine Resin
  • Acetaminophen
  • Fibroblast Growth Factors