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Transcriptional profiling reveals an aberrant hepatic regenerative response underlying acetaminophen (APAP)‐induced acute liver failure (ALF) (LB84)
Author(s) -
Rogler Leslie,
Pattamanuch Nicole,
Bandi Sriram,
Viswanathan Preeti,
Gupta Sanjeev
Publication year - 2014
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.28.1_supplement.lb84
Subject(s) - wnt signaling pathway , liver regeneration , acetaminophen , biology , microrna , axin2 , gene expression profiling , liver x receptor , liver injury , gene expression , drug metabolism , pharmacology , gene , cancer research , microbiology and biotechnology , signal transduction , regeneration (biology) , transcription factor , nuclear receptor , biochemistry , drug
Acetaminophen (APAP) toxicity is the leading cause of ALF in United States. To understand mechanisms in APAP‐induced ALF, we performed transcriptional profiling of healthy livers and severely damaged explanted livers from people receiving liver transplants with Affymetrix Human Genome U133 Plus 2.0 arrays. In parallel, microRNA (miRNA) expression profiles were obtained with µParaflo® technology platform (LC Sciences.com). The most significantly down regulated gene categories were: acute phase response and LXR/RXR signaling, mitochondrial dysfunction, coagulation and complement systems, and xenobiotic metabolism. Genes involved in cholesterol and lipid metabolism or cholesterol, lipid and bile acid transport were globally down regulated. Also, hsa‐mir‐193, ‐26a, ‐23a, ‐122, ‐let7c, ‐92a were significantly down regulated. The gene expression pattern suggested activation of hepatic stellate cells. The biliary marker, KR19, was up regulated, as was the NOTCH ligand, JAG1. The proliferation markers, PCNA and Ki67, were up regulated, although growth inhibitory genes, e.g., PTCH2, TGFB1, PTTG1 and WNT signaling inhibitors, e.g., BICC1, were simultaneously up regulated. Several of these up regulated genes are targeted by miRNAs that we found were down regulated in liver with APAP toxicity. These data indicated that liver regeneration was aberrant and that miRNAs could represent suitable targets for therapeutic intervention in APAP‐induced ALF. Grant Funding Source : NIH and NYSTEM