Acetaminophen (APAP) toxicity is the leading cause of acute liver failure (ALF) in United States. To understand mechanisms in APAP-induced ALF, researchers from the Albert Einstein College of Medicine 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 with LC Sciences’ miRNA microarray services. They found 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 found to be 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. Their data indicated that liver regeneration was aberrant and that miRNAs could represent suitable targets for therapeutic intervention in APAP-induced ALF.

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Reference

Leslie Rogler, Nicole Pattamanuch, Sriram Bandi, Preeti Viswanathan, Sanjeev Gupta. Transcriptional profiling reveals an aberrant hepatic regenerative response underlying acetaminophen (APAP)-induced acute liver failure (ALF) (2014) FASEB 28(1): LB84. [article]