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Bile acid depletion increases susceptibility to acetaminophen‐induced hepatotoxicity in mice
Author(s) -
Bhushan Bharat,
Borude Prachi,
Edwards Genea,
Walesky Chad,
Cleveland Joshua,
Li Feng,
Ma Xiaochao,
Apte Udayan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.387.1
Subject(s) - acetaminophen , bile acid , liver injury , cholestyramine , medicine , endocrinology , chemistry , liver regeneration , metabolism , hepatoprotection , pharmacology , taurocholic acid , biochemistry , enzyme , biology , cholesterol , glutathione , regeneration (biology) , microbiology and biotechnology
Bile acids are known to play significant role in liver homeostasis. However, the role of bile acids in pathogenesis of acetaminophen (APAP)‐induced acute liver failure (ALF) is not known. Here we report that depletion of bile acids using cholestyramine (CSA), a bile acid sequestering resin, increases susceptibility of C57BL6 mice to APAP‐induced hepatotoxicity. C57BL6 mice were fed either normal diet or 2% CSA containing diet for 1 week, treated with 400 mg/kg APAP (ip) and analyzed over a time course of 0 to 24 hr. The CSA‐fed mice developed rapid and higher liver injury after APAP treatment. Depletion of bile acids by CSA did not alter metabolism of APAP. However, CSA‐fed mice exhibited rapid and significantly higher activation of c‐Jun N‐terminal protein Kinase (JNK) following APAP treatment. Furthermore, a significant decrease in intestinal fibroblast growth factor 15 (FGF15) mRNA was observed in CSA fed mice before and after APAP treatment. Compensatory liver regeneration following APAP overdose was delayed in the CSA‐fed mice up to 12 hr but was not different than the normal diet fed mice at 24 hr after APAP treatment. Taken together, these data indicate that depletion of intestinal bile acid increases susceptibility to APAP by rapid and higher hepatic JNK activation. These data indicate that bile acids and FGF15‐mediated gut‐liver signaling axis play an important role in cytoprotection following APAP‐induced ALF. These studies were supported by NIH ‐ P20 RR021940 (Udayan Apte), and AASLD/ALF Liver Scholar Award (Udayan Apte)