The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity.

Florian Schueller,Sanchari Roy,Christoph Roderburg,Tom Luedde,Christian Trautwein,Mihael Vucur

doi:10.3390/ijms19010261

Florian Schueller, Sanchari Roy + Show 4 more

Open Access

https://doi.org/10.3390/ijms19010261

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Abstract

Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine.

Highlights

MicroRNAs are small, non-protein coding, single-stranded RNAs of ~22 nucleotides length, which are transcribed by RNA polymerase II and III
MiR-122 inhibition leads to an upregulation of hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and hepcidin antimicrobial peptide (Hamp), which control systemic iron levels [45]
Hepatic levels of miR-122 are nearly constant, they are associated with circadian gene expression in the liver [46], because knockdown of miR-122 has resulted in dysregulation of many mRNAs, which accumulated in a circadian fashion

Summary

Findings

HCC patients HCC cell lines downregulated miR-122 expression in HCC patients. Expression inversely correlated with presence of metastatic disease and patientsgeneral prognosis miR-122 inhibit proliferation, migration and promotes hepatocyte death [6] [37,38]. HCC cell lines miR-199a suppressed tumour proliferation, induced apoptosis and cell cycle arrest (via regulation of MMP-9, FZD7, HIF1α). Since their discovery in 1993, miRNAs were studied to clarify their physiological role in organ homeostasis, tissue development, and regeneration. Hepatic levels of miR-122 are nearly constant, they are associated with circadian gene expression in the liver [46], because knockdown of miR-122 has resulted in dysregulation of many mRNAs, which accumulated in a circadian fashion. MiRNA expression profiles were linked to hepatocyte proliferation and liver regeneration [47]. AfpCre;Dicer1flox/flox mutants displayed no altered phenotype directly after birth, they developed at 2–4 month of age progressive hepatocyte damage, as seen by increased AST and ALT levels, an increased liver mass accompanied by an increased proliferation and apoptosis [48]. The provided examples demonstrate the diverse role of miRNAs in maintaining liver homeostasis, and highlight miRNA’s involvement in acute and chronic liver diseases

The Role of miRNAs in Acute Liver Toxicity

The Role of miRNAs in Chronic Alcoholic Liver Toxicity

Outlook

Conclusions