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Review
. 2013 Sep;10(9):542-52.
doi: 10.1038/nrgastro.2013.87. Epub 2013 May 21.

MicroRNAs in liver disease

Gyongyi Szabo  1 , Shashi Bala
Affiliations
Review

MicroRNAs in liver disease

Gyongyi Szabo et al. Nat Rev Gastroenterol Hepatol. 2013 Sep.

Abstract

Small, noncoding microRNAs (miRNAs) regulate diverse biological functions in the liver and increasing evidence suggests that they have a role in liver pathology. This Review summarizes advances in the field of miRNAs in liver diseases, inflammation and cirrhosis. MicroRNA-122, the most abundant miRNA in hepatocytes, has well-defined roles in HCV replication, and data indicate that it also serves as a viable therapeutic target. The role of miR-122 is also emerging in other liver diseases. Ample evidence exists for the important regulatory potential of other miRNAs in conditions associated with liver inflammation related to alcohol use, the metabolic syndrome or autoimmune processes. In addition, a broad array of miRNAs have been associated with the development of liver fibrosis both in animal models and human studies. The significance of the function and cellular distribution of miRNAs in the liver and the potential of miRNAs as a means of communication between cells and organs is discussed as well as the emerging utility of circulating miRNAs as biomarkers of different forms of liver damage and as early markers of disease and progression in hepatocellular carcinoma. Importantly, miRNA modulation in the liver represents a new therapeutic approach in the treatment armamentarium of hepatologists in the future.

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Figures

Figure 1
Figure 1
Biogenesis of miRNAs. miRNAs are transcribed from miRNA genes via RNA polymerase II or III as pri-miRNA and cleaved by DROSHA–DGCR8 complex in the nucleus. The resulting precursor (pre)-miRNA is exported to the cytoplasm via exportin-5 complex. In the cytoplasm, DICER, along with TRBP, cleaves pre-miRNA to form mature miRNA (miRNA duplex). The strand is selected depending upon the stability, and the functional strand is loaded together with Ago2 and GW182 into the RISC. The less stable strand of miRNA gets degraded. Depending on the complementarity of the seed region of mature miRNA to the 3' UTR of the target mRNA gene, target mRNA either undergoes cleavage, translational repression or activation. Abbreviations: RISC, RNA-induced silencing complex; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA.
Figure 2
Figure 2
Role of microRNAs in alcoholic liver disease. Alcohol alone, or along with its metabolites, increases levels of miR-212 in gut epithelial cells, which regulate the tight junction protein, ZO1. Decreases in ZO1 are associated with disruption of gut integrity and thereby increased intestinal permeability and increased bacterial or microbial translocation into the intestinal lumen and a subsequent increase in LPS. The excess of LPS in the liver affects immune (Kupffer cells), parenchymal (hepatocytes), and non-immune cells (endothelial cells). In response, Kupffer cells become activated and induction of miR-155 and release of TNF takes place. TNF causes further injury to hepatocytes and damaged hepatocytes release danger molecules, including miR-122, which are recognized by various immune cells; amplification of inflammation takes place. Alcohol intake also increases oxidative stress, which results in the upregulation of miR-34a and miR-217 and perhaps decrease in miR-122 in hepatocytes. Dysregulation of these miRNAs results in hepatic steatosis via SIRT1 and many other unidentified genes. Oxidative stress downregulates miR-199a in endothelial cells, which results in increase of ET1 and HIF-1α, both of which are genes that contribute to liver inflammation, steatosis and perhaps fibrosis. Abbreviation: LPS, lipopolysaccharide; ROS, reactive oxygen species; TLR4, Toll-like receptor 4; TNFR, tumour necrosis factor receptor.
Figure 3
Figure 3
MicroRNAs in chronic HCV infection. HCV infects hepatocytes and a unique interaction take place between host miR-122 and HCV 5’UTR along with proteins of RISC (Ago2, GW182 and HSPs), which results in enhanced replication of HCV virus. Other host factors, such as cyclinG1 (miR-122 target), are also involved in enhanced HCV replication in the presence of alcohol. HCV infection modulates other host miRNAs, leading to an increase in levels of miR-155 and a decrease in levels of miR-499 in hepatocytes, linking inflammation to cancer via Notch and Wnt signalling. HCV infection causes hepatocyte damage and thereby release of danger molecules, which activate immune cells and enhance local and systemic inflammation. Activation of peripheral monocytes causes an increase in levels of miR-155, which subsequently enhances release of TNF into the circulation. Various miRNAs such as miR-122, miR-155, miR-34a, miR-21, miR-146a and miR-125b are increased in the circulation of patients infected with HCV and might contribute to pathogenesis of the disease. Abbreviations: HSP, heat shock protein; RISC, RNA-induced silencing complex.
Figure 4
Figure 4
Regulation of fibrogenetic events by microRNAs. miRNAs can be profibrotic (miR-199a/b, miR-19 or miR-34) and antifibrotic (such as miR-29, miR-19 and miR-150). miR-221 or miR-27 regulate activation and proliferation of HSCs. miRNAs, such as miR-9, miR-21 and miR-188 are involved in myofibroblast activation and synthesis of extracellular proteins and collagen deposition. Fibrotic changes are also associated with dysregulation of miRNAs in the circulation. Both increased levels (miR-122, miR-34a and miR-571) and decreased levels (miR-652 and miR-181b) of miRNAs have been found in the circulation. Abbreviation: HSC, hepatic stellate cell.
Figure 5
Figure 5
Circulating/extracellular microRNAs as biomarkers of liver disease. Liver damage caused by alcohol, acetaminophen, viral or bacterial infection, chemical toxins and diet results in the release of various miRNAs into the circulation. The circulating miRNAs (mature or precursor) can be released inside exosomes, microvesicles, HDL, apoptotic bodies and with proteins (Ago2). The components of RISC proteins such as Ago2 and its interacting partner GW182 have also been found in exosomes and microvesicles. Abbreviations: RISC, RNA-induced silencing complex.
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