Role of Noncoding RNAs in Acetaminophen-Induced Liver Injury

Abstract

Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these noncoding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of 25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (2125 nucleotides) RNAs that are processed from precursor RNAs that have stemloop structure, whereas noncoding RNAs >200 nucleotides are termed long noncoding RNAs (lncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP-induced liver injury (AILI).

Figure 1

MicroRNAs that are known to modulate acetaminophen metabolism in animal models (miR-122, miR-125b, and miR-22) and in cell (hepatocytes and HepaRG) cultures (miR-27b and miR-375). Arrows and pins denote activation and repression, respectively.

Figure 2

Classification of noncoding RNAs. From Takahashi et al. [Hepatology, 60(2), 744-753, 2014 (10.1002/hep.27043)], reproduced with permission from the publisher.

Figure 3

(A) Northern blot analysis of serum miR-122 and 5S rRNA isolated from the control (miR-122^fl/fl and miR-122 LKO mice injected with APAP or PBS). (B) Survival of control and miR-122 LKO mice injected with APAP (500 mg/kg). (C) Western blot analysis of CYP1A2 and CYP2E1 in the hepatocytes isolated from the control and miR-122 LKO mice. From Chowdhary et al. [Am J Pathol. 187(12), 2758–2774, 2017 (doi: 10.1016/j.ajpath.2017.08.026)], with permission from the publisher.